Mono quaternary ammonium salts and methods for modulating neuronal nicotinic acetylcholine receptors

ABSTRACT

Provided are monoquaternary ammonium compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.

This application claims benefit of U.S. Provisional Application No.60/814,423, filed Jun. 16, 2006, which is incorporated herein byreference in its entirety.

IDENTIFICATION OF FEDERAL FUNDING

The present invention was supported by Grant NIH U19DA017548 from theNational Institutes of Health, and therefore the government may haverights in the invention.

FIELD OF THE INVENTION

The invention relates to monoquaternary ammonium salts and their use inmodulating nicotinic acetylcholine receptors.

BACKGROUND OF THE INVENTION

S(−)-nicotine (NIC) activates presynaptic and postsynaptic neuronalnicotinic receptors that evoke the release of neurotransmitters frompresynaptic terminals and that modulate the depolarization state of thepostsynaptic neuronal membrane, respectively. Thus, nicotine producesits effect by binding to a family of ligand-gated ion channels,stimulated by acetylcholine (ACh) or nicotine which causes the ionchannel to open and cations to flux with a resulting rapid (millisecond)depolarization of the target cell.

Neuronal nicotinic receptors are composed of two types of subunits, αand β, and assemble as heteromeric receptors with the generalstoichiometry of 2α and 3β or as homomeric receptors with 5α subunits.Nine subtypes of the α subunit (α2 to α10) and three subtypes of the βunit (β2 to β4) are found in the central nervous system. The most commonnicotinic receptor subtype in the brain is composed of two α4 and threeβ2 subunits, i.e., α4β2. These subunits display different, butoverlapping, patterns of expression in the brain. Examples ofheteromeric receptor subtypes include α4β2, α3β2, α3β4, α6β2, α4α5β2,α6α5β2, α4α6β2, α4β2β4, α3β2β4, and others. The predominant homomericsubtype includes α7, but other combinations have also been proposed.

For the most part, the actual subunit compositions and stoichiometriesof nicotinic receptors in the brain remain to be elucidated. Thus,neuronal nicotinic receptor subtype diversity originates fromdifferences in the amino acid sequence at the subunit level and from themultiple combinations of assemblies of subunits into functional receptorproteins, which affords a wide diversity of pharmacological specificity.

In spite of the extensive diversity in neuronal nicotinic receptormessenger RNA expression, only a limited number of tools are availableto study the pharmacology of native receptors. Radioligands are used inmany studies. [³H]NIC appears to label the same sites in the brain as[³H]ACh. It has been estimated that over 90% of [³H]NIC binding in thebrain is due to association with the heteromeric receptor that iscomposed of α4 and β2 subunits. Also abundant in the central nervoussystem are the homomeric receptors labeled by [³H]methyllycaconitine(MLA), which has high affinity for the α7 nicotinic receptor subtype.Nicotinic receptor subtypes can be studied using functional assays, suchas NIC-evoked neurotransmitter release (e.g., [³H]dopamine (DA) release,[³H]norepinephrine (NE) release, [³H]serotonin (5-HT) release,[³H]gamma-aminobutyric acid (GABA) release and [³H]glutamate release)from superfused rat brain slices. Nicotinic receptors are located in thecell body and terminal areas of these neurotransmitter systems. NICfacilitates neurotransmitter release from nerve terminals.

The structural and functional diversity of central nervous systemnicotinic receptors has stimulated a great deal of interest indeveloping novel, subtype-selective agonists and/or antagonists. Some ofthese agonists are currently being evaluated in clinical trials forcognitive enhancement and neuroprotective effects, potentiallybeneficial for disease states such as Alzheimer's and Parkinson'sdisease.

SUMMARY OF THE INVENTION

In one embodiment, compounds corresponding to the following structureare provided.

A¹, A², A³, A⁴, and A⁵ are independently selected from nitrogen orcarbon, provided that when nitrogen is present, the nitrogen does nothave an R substituent attached.

R¹, R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heterocycle, substitutedheterocycle, halo, cyano, and nitro, or R¹ and R² or R² and R³ togetherwith the carbons to which they are attached independently form a threeto eight-member cycloalkane, substituted cycloalkane, cycloalkene,substituted cycloalkene, aryl, substituted aryl, heterocycle with one tothree hetero atoms in the ring, or substituted heterocycle with one tothree hetero atoms in the ring.

Z¹ is absent or is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenylene,substituted phenylene, alkoxy, and substituted alkoxy.

Z² is selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, arylene, substituted arylene, heterocycle,substituted heterocycle, alkoxy, and substituted alkoxy.

Z³ is selected from is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, andsubstituted heterocycle.

X⁻ is an inorganic or organic anion.

In another embodiment, a composition is provided comprising apharmaceutically acceptable carrier and a compound as described above.

In another embodiment, a method is provided for selectively modulatingthe function of a nicotinic acetylcholine receptor comprisingadministering a therapeutically effective amount of a compound asdescribed above to a mammalian subject in need thereof.

In another embodiment, a method is provided for preventing and/ortreating a central nervous system associated disorder comprisingadministering a therapeutically effective amount of a compound asdescribed above to a mammalian subject in need thereof.

In another embodiment, a method is provided for preventing and/ortreating substance use and/or abuse comprising administering atherapeutically effective amount of a compound as described above to amammalian subject in need thereof.

In another embodiment, a method is provided for preventing and/ortreating gastrointestinal tract disorders comprising administering atherapeutically effective amount of a compound as described above to amammalian subject in need thereof.

Other methods, features and advantages of the present invention will beor become apparent to one with skill in the art upon examination of thefollowing detailed descriptions. It is intended that all such additionalmethods, features and advantages be included within this description, bewithin the scope of the present invention, and be protected by theaccompanying claims.

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions and methods are described, it is to beunderstood that the invention is not limited to the particularmethodologies, protocols, assays, and reagents described, as these mayvary. It is also to be understood that the terminology used herein isintended to describe particular embodiments of the present invention,and is in no way intended to limit the scope of the present invention asset forth in the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural references unless thecontext clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All publications citedherein are incorporated herein by reference in their entirety for thepurpose of describing and disclosing the methodologies, reagents, andtools reported in the publications that might be used in connection withthe invention. Nothing herein is to be construed as an admission thatthe invention is not entitled to antedate such disclosure by virtue ofprior invention.

The term “nicotinic acetylcholine receptor” refers to the endogenousacetylcholine receptor having binding sites for acetylcholine which alsobind to nicotine. The term “nicotinic acetylcholine receptor” includesthe term “neural nicotinic acetylcholine receptor.”

The terms “subtype of nicotinic acetylcholine receptor,” and “nicotinicacetylcholine receptor subtype” refer to various subunit combinations ofthe nicotinic acetylcholine receptor, and may refer to a particularhomomeric or heteromeric complex, or multiple homomeric or heteromericcomplexes.

The term “agonist” refers to a substance which interacts with a receptorand increases or prolongs a physiological response (i.e. activates thereceptor).

The term “partial agonist” refers to a substance which interacts withand activates a receptor to a lesser degree than an agonist.

The term “antagonist” refers to a substance which interacts with anddecreases the extent or duration of a physiological response of thatreceptor.

The terms “disorder,” “disease,” and “condition” are used inclusivelyand refer to any status deviating from normal.

The term “central nervous system associated disorders” includes anycognitive, neurological, and mental disorders causing aberrant orpathological neural signal transmission, such as disorders associatedwith the alteration of normal neurotransmitter release in the brain.

The term “lower alkyl” refers to straight or branched chain alkylradicals having in the range of 1 to 4 carbon atoms.

The term “alkyl” refers to straight or branched chain alkyl radicalshaving 1 to 19 carbon atoms, and “substituted alkyl” refers to alkylradicals further bearing one or more substituents including, but notlimited to, hydroxy, alkoxy (of a lower alkyl group), mercapto (of alower alkyl group), aryl, heterocyclic, halogen, trifluoromethyl, cyano,nitro, amino, carboxyl, carbamate, sulfonyl, and sulfonamide.

The term “cycloalkyl” refers to cyclic ring-containing moietiescontaining 3 to 8 carbon atoms, and “substituted cycloalkyl” refers tocycloalkyl moieties further bearing one or more substituents as setforth above.

The term “alkenyl” refers to straight or branched chain hydrocarbylgroups having at least one carbon-carbon double bond and having 2 to 19carbon atoms, and “substituted alkenyl” refers to alkenyl groups furtherbearing one or more substituents as set forth above.

The term “alkynyl” refers to straight or branched chain hydrocarbylmoieties having at least one carbon-carbon triple bond and having 2 to19 carbon atoms, and “substituted alkynyl” refers to alkynyl moietiesfurther bearing one or more substituents as set forth above.

The term “aryl” refers to aromatic groups having 6 to 24 carbon atoms,and “substituted aryl” refers to aryl groups further bearing one or moresubstituents as set forth above.

The term “heterocyclic” refers to cyclic moieties containing one or moreheteroatoms as part of the ring structure and having 3 to 24 carbonatoms, and “substituted heterocyclic” refers to heterocyclic moietiesfurther bearing one or more substituents as set forth above.

The term “halogen” refers to fluoride, chloride, bromide or iodidegroups. It is understood that in all substituted groups defined above,polymers arrived at by defining substituents with further substituentsto themselves (e.g. substituted aryl having a substituted aryl group asa substituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. In such cases, the maximumnumber of such substituents is three. That is to say that each of theabove definitions is constrained by a limitation that, for example,substituted aryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Compounds of the present invention are mono quaternary ammonium saltscorresponding to Formula (I):

A¹, A², A³, A⁴, and A⁵ are independently selected from nitrogen orcarbon, provided that when nitrogen is present, the nitrogen does nothave an R substituent attached.

R¹, R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heterocycle, substitutedheterocycle, halo, cyano, and nitro, or R¹ and R² or R² and R³ togetherwith the carbons to which they are attached independently form a threeto eight-member cycloalkane, substituted cycloalkane, cycloalkene,substituted cycloalkene, aryl, substituted aryl, heterocycle with one tothree hetero atoms in the ring, or substituted heterocycle with one tothree hetero atoms in the ring.

Z¹ is absent or is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenylene,substituted phenylene, alkoxy, and substituted alkoxy.

Z² is selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, arylene, substituted arylene, heterocycle,substituted heterocycle, alkoxy, and substituted alkoxy.

Z³ is selected from is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, andsubstituted heterocycle.

X⁻ is an inorganic or organic anion.

For example, R¹, R², R³, R⁴, and R⁵ include hydrogen, methyl, ethyl,propyl, butyl, trifluoromethyl, pyrrolidine, N-alkyl pyrrolidine (forexample where the alkyl chain is methyl, ethyl or propyl), unsaturatedpyrrolidine, unsaturated N-alkyl pyrrolidine (for example where thealkyl chain is methyl, ethyl or propyl), aziridine, N-methyl aziridine,azetidine, N-methyl azetidine, unsaturated azetidine, unsaturatedN-methyl azetidine, piperidine, N-methyl piperidine, unsaturatedpiperidine, unsaturated N-methyl piperidine, azepane, N-methyl azepane,unsaturated azepane, unsaturated N-methyl azepane, azocane, N-methylazocane, unsaturated azocane, unsaturated N-methyl azocane,1-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.1]heptane,8-methyl-8-aza-bicyclo[3.2.1]octane,1-aza-tricyclo[3.3.1.1^(3,7)]decane, methyl cycloalkyl, methylsubstituted cycloalkyl, methylpyrrolidine, methyl N-alkyl pyrrolidine(for example where the alkyl chain is methyl, ethyl or propyl), methylunsaturated pyrrolidine, methyl unsaturated N-alkyl pyrrolidine (forexample where the alkyl chain is methyl, ethyl or propyl), methylaziridine, methyl N-methyl aziridine, methyl azetidine, methyl N-methylazetidine, methyl unsaturated azetidine, methyl unsaturated N-methylazetidine, methyl piperidine, methyl N-methyl piperidine, methylunsaturated piperidine, methyl unsaturated N-methyl piperidine, methylazepane, methyl N-methyl azepane, methyl unsaturated azepane, methylunsaturated N-methyl azepane, methyl azocane, methyl N-methyl azocane,methyl unsaturated azocane, methyl unsaturated N-methyl azocane,methyl-1-aza-bicyclo[3.2.1]octane, methyl-1-aza-bicyclo[2.2.1]heptane,8-methyl-8-aza-bicyclo [3.2.1]octane, andmethyl-1-aza-tricyclo[3.3.1.1^(3,7)]decane.

As another example, when R¹ and R², or R² and R³ together with thecarbons to which they are attached, independently form a three toeight-membered ring, that ring may be a heterocycle containing up tothree hetero atoms (for example nitrogen, oxygen or sulfur) in the ring,and further may be substituted with one or more substituents. Forexample, possible rings include benzene, pyridine, pyran, indene,isoindene, benzofuran, isobenzofuran, benzo[b]thiophene,benzo[c]thiophene, indole, indolenine, isoindole,cyclopental[b]pyridine, pyrano[3,4-b]pynrole, indazole, indoxazine,benzoxazole, anthranil naphthalene, tetralin, decalin, chromene,coumarin, chroman-4-one, isocoumarin, isochromen-3-one, quinoline,isoquinoline, cinnoline, quinazoline, naphthyrdine,pyrido[3,4-b]-pyridine, pyridol[3,2-b]pyridine, pyrido[4,3,-b]-pyridine,benzoxazine, anthracene, phenanthrene, phenalene, fluorene, carazole,xanthene, acnidine, octahydro-[1]pyridine, 1-methyloctahydro-[1]pyrdine,octahydroindole, 1-methyloctahydro-indole,octahydro-cyclopenta[b]pyrrole, 1-methyloctahydro-cyclopenta[b]pyrrole,decahydroquinoline, or 1-methyldecahydroquinoline.

As a further example, heterocycles formed by A¹, A², A³, A⁴, and A⁵ incombination with R¹, R², R³, R⁴, and R⁵ include pyridine, quinoline,5,6,7,8-tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline,pyrazine, pyrimidine, pyridazine, and triazine, as well as substitutedforms thereof.

Z¹ for example includes alkyl (for example butyl or pentyl),cis-alkenyl; trans-alkenyl; substituted cis-alkenyl; substitutedtrans-alkenyl; alkynyl (for example but-3-ynyl or pent-4-ynyl).

Z² for example includes cis-alkenyl, trans-alkenyl, substitutedcis-alkenyl, and substituted trans-alkenyl.

X⁻ for example includes Cl⁻, Br⁻, I⁻, NO₂ ⁻, HSO₄ ⁻, SO₄ ⁻, HPO₄ ⁻, PO₄²⁻, ethanesulfonate, trifluoromethane sulfate, p-toluenesulfonate,benzenesulfonate, salicylate, proprionate, ascorbate, aspartate,fumarate, galactarate, maleate, citrate, glutamate, glycolate, lactate,malate, maleate, tartrate, oxalate, succinate, or similarpharmaceutically acceptable organic acid addition salts, including thepharmaceutically acceptable salts listed in the Journal ofPharmaceutical Sciences volume 66, page 2, 1977, which are herebyincorporated by reference. The above salt forms may be in some caseshydrates or solvates with alcohols and other solvents.

In a compound of Formula (I), preferably A¹, A², A³, A⁴, and A⁵ arecarbon.

In a compound of Formula (I), preferably R¹ is hydrogen, alkyl, or formsa six membered ring with A¹, A² and R² and with R¹ and R² providing fourcarbon atoms. More preferably, R¹ is selected from hydrogen, methyl,forms a six membered ring with A¹, A² and R² and with R¹ and R²providing four unsaturated carbon atoms, or forms a phenyl group withA¹, A² and R².

In a compound of Formula (I), preferably R² is hydrogen, alkyl, aryl,3-hydroxypropyl, 1-methyl-2-pyrrolidinyl, halo, forms a six memberedring with A¹, A² and R¹ and with R¹ and R² providing four carbon atoms,or forms a six membered ring with A², A³ and R³ and with R² and R³providing four carbon atoms. More preferably, R² is hydrogen, methyl,ethyl, butyl, phenyl, 3-hydroxypropyl, 1-methyl-2-pyrrolidinyl, bromo,forms a six membered ring with A¹, A² and R¹ and with R¹ and R²providing four unsaturated carbon atoms, forms a phenyl group with A¹,A² and R¹, forms a six membered ring with A², A³ and R³ and with R² andR³ providing four unsaturated carbon atoms, or forms a phenyl group withA², A³ and R³.

In a compound of Formula (I), preferably R³ is hydrogen, alkyl, or formsa six membered ring with A², A³ and R² and with R² and R³ providing fourcarbon atoms. More preferably, R³ is hydrogen, methyl, forms a sixmembered ring with A², A³ and R² and with R² and R³ providing fourunsaturated carbon atoms, or forms a phenyl group with A², A³ and R².

In a compound of Formula (I), preferably R⁴ is hydrogen or alkyl. Morepreferably, R⁴ is hydrogen or methyl.

In a compound of Formula (I), preferably R⁵ is hydrogen.

In a compound of Formula (I), preferably Z¹ is absent, or is alkyl,alkynyl, or alkoxy. More preferably, Z¹ is absent, butyl, but-3-ynyl,pentyl, pent-4-ynyl or 2-ethoxy.

In a compound of Formula (I), preferably Z² is alkyl, arylenyl oralkoxy. More preferably, Z² is hexyl, octyl, dodecyl, tridecyl,para-phenylene, or 2-ethoxy.

In a compound of Formula (I), preferably Z³ is alkyl, alkynyl, aryl orheterocyclic. More preferably Z³ is propyl, butyl, but-1-ynyl,hex-1-ynyl, phenyl, or 3-pyridinyl.

In a compound of Formula (I), preferably X is a halogen. Morepreferably, X is chloride, bromide or iodide.

In one embodiment, the compound of Formula (I) is defined wherein A¹,A², A³, A⁴, and A⁵ are carbon; wherein R¹ is hydrogen, methyl, forms asix membered ring with A¹, A² and R² and with R¹ and R² providing fourunsaturated carbon atoms, or forms a phenyl group with A¹, A² and R²;wherein R² is hydrogen, methyl, ethyl, butyl, phenyl, 3-hydroxypropyl,1-methyl-2-pyrrolidinyl, bromo, forms a six membered ring with A¹, A²and R¹ and with R¹ and R² providing four unsaturated carbon atoms, formsa phenyl group with A¹, A² and R¹, forms a six membered ring with A², A³and R³ and with R² and R³ providing four unsaturated carbon atoms, orforms a phenyl group with A², A³ and R³; wherein R³ is hydrogen, methyl,forms a six membered ring with A², A³ and R² and with R² and R³providing four unsaturated carbon atoms, or forms a phenyl group withA², A³ and R²; wherein R⁴ is hydrogen or methyl; wherein R⁵ is hydrogen;wherein Z¹ is absent, butyl, but-3-ynyl, pentyl, pent-4-ynyl or2-ethoxy; wherein Z² is hexyl, octyl, dodecyl, tridecyl, para-phenylene,or 2-ethoxy; wherein Z³ is propyl, butyl, but-1-ynyl, hex-1-ynyl,phenyl, or 3-pyridinyl; and wherein X is chloride, bromide or iodide.

In another embodiment, the compound of Formula (I) is defined whereinA¹, A², A³, A⁴, and A⁵ are carbon; wherein R¹ is hydrogen, methyl, formsa six membered ring with A¹, A² and R² and with R¹ and R² providing fourunsaturated carbon atoms, or forms a phenyl group with A¹, A² and R²;wherein R² is hydrogen, methyl, ethyl, 3-hydroxypropyl,1-methyl-2-pyrrolidinyl, bromo, forms a six membered ring with A¹, A²and R¹ and with R¹ and R² providing four unsaturated carbon atoms, formsa phenyl group with A¹, A² and R¹, forms a six membered ring with A², A³and R³ and with R² and R³ providing four unsaturated carbon atoms, orforms a phenyl group with A², A³ and R³; wherein R³ is hydrogen, methyl,forms a six membered ring with A², A³ and R² and with R² and R³providing four unsaturated carbon atoms, or forms a phenyl group withA², A³ and R²; wherein R⁴ is hydrogen or methyl; wherein R⁵ is hydrogen;wherein Z¹ is absent, butyl, but-3-ynyl, pent-4-ynyl or 2-ethoxy;wherein Z² is hexyl, octyl, dodecyl, tridecyl, para-phenylene, or2-ethoxy; wherein Z³ is propyl, butyl, but-1-ynyl, hex-1-ynyl, phenyl,or 3-pyridinyl; and wherein X is chloride, bromide or iodide.

In another embodiment, the compound of Formula (I) is defined whereinA¹, A², A³, A⁴, and A⁵ are carbon; wherein R¹ is hydrogen, methyl, orforms a phenyl group with A¹, A² and R²; wherein R² is hydrogen, methyl,butyl, phenyl, 1-methyl-2-pyrrolidinyl, forms a phenyl group with A¹, A²and R¹, or forms a phenyl group with A², A³ and R³; wherein R³ ishydrogen, methyl, or forms a phenyl group with A², A³ and R²; wherein R⁴is hydrogen or methyl; wherein R⁵ is hydrogen; wherein Z¹ is pentyl orpent-4-ynyl; wherein Z² is para-phenylene; wherein Z³ is phenyl; andwherein X is bromide.

Exemplary compounds for this application are presented in Table 1.

TABLE 1

ID # R¹ R² R³ R⁴ Z¹ Z² Z³ X GZ-565A H Me H H but-3-ynyl p-phenyl phenylbromide GZ-565B Me H H H but-3-ynyl p-phenyl phenyl bromide GZ-565C H HMe H but-3-ynyl p-phenyl phenyl bromide GZ-566A H Me H Me but-3-ynylp-phenyl phenyl bromide GZ-566B H Me Me H but-3-ynyl p-phenyl phenylbromide GZ-566C Me H Me H but-3-ynyl p-phenyl phenyl bromide GZ-567Aphenyl with R² phenyl with R¹ H H but-3-ynyl p-phenyl phenyl bromideGZ-567B H phenyl with R³ phenyl with R² H but-3-ynyl p-phenyl phenylbromide GZ-567C H 1-methyl-2- H H but-3-ynyl p-phenyl phenyl bromidepyrrolidinyl GZ-568A H butyl H H but-3-ynyl p-phenyl phenyl bromideGZ-568B H phenyl H H but-3-ynyl p-phenyl phenyl bromide GZ-568C H H H Hbut-3-ynyl p-phenyl phenyl bromide GZ-573A H Me H H butyl p-phenylphenyl bromide GZ-573B Me H H H butyl p-phenyl phenyl bromide GZ-573C HH Me H butyl p-phenyl phenyl bromide GZ-574A H Me H Me butyl p-phenylphenyl bromide GZ-574B H Me Me H butyl p-phenyl phenyl bromide GZ-574CMe H Me H butyl p-phenyl phenyl bromide GZ-575A phenyl with R² phenylwith R¹ H H butyl p-phenyl phenyl bromide GZ-575B H phenyl with R³phenyl with R² H butyl p-phenyl phenyl bromide GZ-575C H 1-methyl-2- H Hbutyl p-phenyl phenyl bromide pyrrolidinyl GZ-576A H butyl H H butylp-phenyl phenyl bromide GZ-576B H H H H butyl p-phenyl phenyl bromideZZ-1-101 H 3- H H propyl p-phenyl butyl bromide hydroxypropyl ZZ-1-104Me H H H propyl p-phenyl butyl bromide ZZ-1-107 Me H Me H propylp-phenyl butyl bromide ZZ-1-137A H Me H H — dodecyl 3-pyridinyl bromideZZ-1-137C H Me H Me — dodecyl 3-pyridinyl bromide ZZ-1-137D H Me Me H —dodecyl 3-pyridinyl bromide ZZ-1-137F H ring with R³, ring with R², H —dodecyl 3-pyridinyl bromide R² & R³ R² & R³ provide 4 provide 4unsaturated unsaturated carbons carbons ZZ-1-26 H H Me H — hexylhex-1-ynyl iodide ZZ-1-29 H 1-methyl-2- H H — hexyl hex-1-ynyl iodidepyrrolidinyl ZZ-1-40A H Me H H methoxy 2-ethoxy hexyl chloride ZZ-1-40BH H Me H methoxy 2-ethoxy hexyl chloride ZZ-1-40C H Me Me H methoxy2-ethoxy hexyl chloride ZZ-1-40D H Me H Me methoxy 2-ethoxy hexylchloride ZZ-1-40E Me H H H methoxy 2-ethoxy hexyl chloride ZZ-1-40F Me HMe H methoxy 2-ethoxy hexyl chloride ZZ-1-40G ring with R², ring withR¹, H H methoxy 2-ethoxy hexyl chloride R¹ & R² R¹ & R² provide 4provide 4 unsaturated unsaturated carbons carbons ZZ-1-40H H ring withR³, ring with R², H methoxy 2-ethoxy hexyl chloride R² & R³ R² & R³provide 4 provide 4 unsaturated unsaturated carbons carbons ZZ-1-40I H1-methyl-2- H H methoxy 2-ethoxy hexyl chloride pyrrolidinyl ZZ-1-40J Hhydroxypropyl H H methoxy 2-ethoxy hexyl chloride ZZ-1-47 H Me H H —heptyl phenyl bromide ZZ-1-48 H H Me H — heptyl phenyl bromide ZZ-1-49Me H H H — heptyl phenyl bromide ZZ-1-50 Me H Me H — heptyl phenylbromide ZZ-1-70 H Me H H prop-2-ynyl p-phenyl butyl bromide ZZ-1-71 H HMe H prop-2-ynyl p-phenyl butyl bromide ZZ-1-71A H Me H H but-3-ynylp-phenyl propyl bromide ZZ-1-71B Me H H H but-3-ynyl p-phenyl propylbromide ZZ-1-71C H H Me H but-3-ynyl p-phenyl propyl bromide ZZ-1-71D HMe Me H but-3-ynyl p-phenyl propyl bromide ZZ-1-71E H Me H Me but-3-ynylp-phenyl propyl bromide ZZ-1-71F Me H Me H but-3-ynyl p-phenyl propylbromide ZZ-1-71H H ring with R³, ring with R², H but-3-ynyl p-phenylpropyl bromide R² & R³ R² & R³ provide 4 provide 4 unsaturatedunsaturated carbons carbons ZZ-1-72 H Me H Me prop-2-ynyl p-phenyl butylbromide ZZ-1-73 H Me Me H prop-2-ynyl p-phenyl butyl bromide ZZ-1-74 Hring with R³, ring with R², H prop-2-ynyl p-phenyl butyl bromide R² & R³R² & R³ provide 4 provide 4 unsaturated unsaturated carbons carbonsZZ-1-76 H Et H H prop-2-ynyl p-phenyl butyl bromide ZZ-1-77 Hhydroxypropyl H H prop-2-ynyl p-phenyl butyl bromide ZZ-1-77A H Me H H —undecyl 3-pyridinyl bromide ZZ-1-77B H H Me H — undecyl 3-pyridinylbromide ZZ-1-77C H Br H H — undecyl 3-pyridinyl bromide ZZ-1-77D H Me MeH — undecyl 3-pyridinyl bromide ZZ-1-77E H Me H Me — undecyl 3-pyridinylbromide ZZ-1-77F H 1-methyl-2- H H — undecyl 3-pyridinyl bromidepyrrolidinyl ZZ-1-94 H Me H H propyl p-phenyl butyl bromide ZZ-1-95 H HMe H propyl p-phenyl butyl bromide ZZ-1-96 H Me H Me propyl p-phenylbutyl bromide ZZ-1-97 H Me Me H propyl p-phenyl butyl bromide ZZ-1-98 Hring with R³, ring with R², H propyl p-phenyl butyl bromide R² & R³ R² &R³ provide 4 provide 4 unsaturated unsaturated carbons carbons ZZU-1 MeH H H — hexyl hex-1-ynyl iodide ZZU-2 H Me H H — hexyl hex-1-ynyl iodideZZU-3 Me H Me H — hexyl hex-1-ynyl iodide ZZU-4 H Me H Me — hexylhex-1-ynyl iodide ZZU-5 H Me Me H — hexyl hex-1-ynyl iodide ZZU-6 Me H HH — octyl but-1-ynyl bromide ZZU-7 H Me H H — octyl but-1-ynyl bromideZZU-8 H H Me H — octyl but-1-ynyl bromide

Exemplary compounds of the present invention include:2-methyl-1-(8-phenyl-octyl)-pyridinium bromide;3-methyl-1-(8-phenyl-octyl)-pyridinium bromide;2,4-dimethyl-1-(8-phenyl-octyl)-pyridinium bromide;4-methyl-1-(8-phenyl-octyl)-pyridinium bromide;1-dodec-7-ynyl-2-methyl-pyridinium iodide;1-dodec-7-ynyl-3-methyl-pyridinium iodide;1-dodec-7-ynyl-4-methyl-pyridinium iodide;1-dodec-7-ynyl-2,4-dimethyl-pyridinium iodide;1-dodec-7-ynyl-3,5-dimethyl-pyridinium iodide;1-dodec-7-ynyl-3,4-dimethyl-pyridinium iodide;1-dodec-9-ynyl-2-methyl-pyridinium bromide;1-dodec-9-ynyl-3-methyl-pyridinium bromide;1-dodec-9-ynyl-4-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-2-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-4-methyl-pyridinium bromide;2-[4-(4-butyl-phenyl)-butyl]-5,6,7,8-tetrahydro-isoquinolinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3-(3-hydroxy-propyl)-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-2,4-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3,4-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3,5-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-4-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-ethyl-pyridinium bromide;2-[4-(4-butyl-phenyl)-but-3-ynyl]-5,6,7,8-tetrahydro-isoquinoliniumbromide; 1-[4-(4-butyl-phenyl)-but-3-ynyl]-3,4-dimethyl-pyridiniumbromide; 1-[4-(4-butyl-phenyl)-but-3-ynyl]-3,5-dimethyl-pyridiniumbromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-(3-hydroxy-propyl)-pyridiniumbromide; 3-methyl-1-[13-(3-pyridinyl)-tridecyl]-pyridinium bromide;3,4-dimethyl-1-[13-(3-pyridinyl)-tridecyl]-pyridinium bromide;3,5-dimethyl-1-[13-(3-pyridinyl)-tridecyl]-pyridinium bromide;2-[13-(3-pyridinyl)-tridecyl]-5,6,7,8-tetrahydro-isoquinolinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-2-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-4-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-2,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3,5-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-quinolinium bromide;2-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-isoquinolinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-butyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-phenyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-1-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-2-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-4-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-2,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3,5-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-quinolinium bromide;2-[5-(1,1′-biphenyl-4-yl)-pentyl]-isoquinolinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-butyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-pyridinium bromide;1-dodec-7-ynyl-3-(1-methyl-2-pyrrolidinyl)-pyridinium iodide;3-methyl-1-[4-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;2-methyl-1-[4-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;4-methyl-1-[4-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;3,4-dimethyl-1-[4-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;3,5-dimethyl-1-[4-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;2,4-dimethyl-1-[4-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;2-[4-(4-propyl-phenyl)-pent-4-ynyl]-5,6,7,8-tetrahydro-isoquinoliniumbromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-(1-methyl-2-pyrrolidinyl)-pyridiniumbromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-(1-methyl-2-pyrrolidinyl)-pyridiniumbromide; 1-[2-(2-hexoxy-ethoxy)-ethyl]-3-methyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-4-methyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-3,4-dimethyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-3,5-dimethyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-2-methyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-2,4-dimethyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-5,6,7,8-tetrahydro-quinolinium chloride;2-[2-(2-hexoxy-ethoxy)-ethyl]-5,6,7,8-tetrahydro-isoquinoliniumchloride; 1-[2-(2-hexoxy-ethoxy)-ethyl]-3-methyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-3-methyl-pyridinium chloride;3-methyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;4-methyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;3-bromo-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;3,4-dimethyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;3,5-dimethyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide; and3-(1-methyl-2-pyrrolidinyl)-1-[12-(3-pyridinyl)-dodecyl]-pyridiniumbromide.

The compounds of the present invention may contain one or morestereocenters. The invention includes all possible diastereomers and allenantiomeric forms as well as racemic mixtures. The compounds can beseparated into substantially optically pure compounds.

The compounds of the invention are nicotinic acetylcholinereceptoragents. Thus, they may augment or inhibit[³H]nicotine binding, [³H]MLAbinding, evoke or inhibit neurotransmitter release, and/or evoke orinhibit the flux of ions through the nicotinic receptor.

In one embodiment, the present invention relates to a method forselectively modulating the function of a nicotinic acetylcholinereceptor comprising administering to a mammalian subject in need thereofa therapeutically effective amount of a compound of Formula (I). In sucha method, the compound of Formula (I) may selectively bind to one ormore subtypes of nicotinic acetylcholine receptor. The compound ofFormula (I) may act as an agoinst or partial agonist of nicotinicacetylcholine receptor function. Hence the compound of Formula (I) mayincrease or prolong the release of a neurotransmitter from a centralnervous system tissue. The neurotransmitter affected may includedopamine, norepinephrine, serotonin, gamma-aminobutryic acid, orglutamate. Alternatively, the compound of Formula (I) may act as anantagonist of nicotinic acetylcholine receptor function. Hence thecompound of Formula (I) may decrease the extent or duration of therelease of a neurotransmitter from a central nervous system tissue. Theneurotransmitter affected may include dopamine, norepinephrine,serotonin, gamma-aminobutryic acid, or glutamate.

In another embodiment, the present invention is directed to a method forpreventing and/or treating a central nervous system associated disordercomprising administering to a mammalian subject in need thereof atherapeutically effective amount of a compound of Formula (I). In such amethod, the compound of Formula (I) may selectively bind to one or moresubtypes of nicotinic acetylcholine receptor. The compound of Formula(I) may act as an agoinst or partial agonist of nicotinic acetylcholinereceptor function. Hence the compound of Formula (I) may increase orprolong the release of a neurotransmitter from a central nervous systemtissue. The neurotransmitter affected may include dopamine,norepinephrine, serotonin, gamma-aminobutryic acid, or glutamate.Alternatively, the compound of Formula (I) may act as an antagonist ofnicotinic acetylcholine receptor function. Hence the compound of Formula(I) may decrease the extent or duration of the release of aneurotransmitter from a central nervous system tissue. Theneurotransmitter affected may include dopamine, norepinephrine,serotonin, gamma-aminobutryic acid, or glutamate.

Central nervous system disorders which may be treated according to themethod of the present invention include Alzheimer's disease, dementia,cognitive dysfunctions (including disorders of attention, focus andconcentration), attention deficit disorders, affective disorders,extrapyramidal motor function disorders, Parkinson's disease,progressive supramolecular palsy, Huntington's disease, Gilles de laTourette syndrome, tardive dyskinesia, neuroendocrine disorders,dysregulation of food intake, disorders of nociception, pain, mood andemotional disorders, depression, panic anxiety, psychosis,schizophrenia, or epilepsy.

In yet another embodiment, the present invention is directed to a methodfor preventing and/or treating substance use and/or abuse comprisingadministering to a mammalian subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I). In such a method, thecompound of Formula (I) may selectively bind to one or more subtypes ofnicotinic acetylcholine receptor. The compound of Formula (I) may act asan agoinst or partial agonist of nicotinic acetylcholine receptorfunction. Hence the compound of Formula (I) may increase or prolong therelease of a neurotransmitter from a central nervous system tissue. Theneurotransmitter affected may include dopamine, norepinephrine,serotonin, gamma-aminobutryic acid, or glutamate. Alternatively, thecompound of Formula (I) may act as an antagonist of nicotinicacetylcholine receptor function. Hence the compound of Formula (I) maydecrease the extent or duration of the release of a neurotransmitterfrom a central nervous system tissue. The neurotransmitter affected mayinclude dopamine, norepinephrine, serotonin, gamma-aminobutryic acid, orglutamate.

The conditions of substance use and/or abuse treated according to themethod of the present invention include nicotine abuse (including use insmoking cessation therapy), nicotine intoxication, amphetamine abuse,methamphetamine abuse, cocaine abuse, or alcohol abuse.

In another embodiment, the present invention is directed to a method forpreventing and/or treating gastrointestinal tract disorders comprisingadministering to a mammalian subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I). In such a method, thecompound of Formula (I) may selectively bind to one or more subtypes ofnicotinic acetylcholine receptor. The compound of Formula (I) may act asan agoinst or partial agonist of nicotinic acetylcholine receptorfunction. Hence the compound of Formula (I) may increase or prolong therelease of a neurotransmitter from a central nervous system tissue. Theneurotransmitter affected may include dopamine, norepinephrine,serotonin, gamma-aminobutryic acid, or glutamate. Alternatively, thecompound of Formula (I) may act as an antagonist of nicotinicacetylcholine receptor function. Hence the compound of Formula (I) maydecrease the extent or duration of the release of a neurotransmitterfrom a central nervous system tissue. The neurotransmitter affected mayinclude dopamine, norepinephrine, serotonin, gamma-aminobutryic acid, orglutamate.

Gastrointestinal disorders which may be treated according to the methodof the present invention include irritable bowel syndrome, colitis,diarrhea, constipation, gastric acid secretion or ulcers.

The compounds of the present invention can be delivered directly or inpharmaceutical compositions along with suitable carriers or excipients,as is well known in the art. For example, a pharmaceutical compositionof the invention may include a conventional additive, such as astabilizer, buffer, salt, preservative, filler, flavor enancer and thelike, as known to those skilled in the art. Exemplary buffers includephosphates, carbonates, citrates and the like. Exemplary preservativesinclude EDTA, EGTA, BHA, BHT and the like.

An effective amount of such agents can readily be determined by routineexperimentation, as can the most effective and convenient route ofadministration and the most appropriate formulation. Variousformulations and drug delivery systems are available in the art. See,e.g., Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, nasal, or intestinal administration and parenteraldelivery, including intramuscular, subcutaneous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intravenous, intraperitoneal, intranasal, or intraocular injections. Theagent or composition thereof may be administered in a local rather thana systemic manner. For example, a suitable agent can be delivered viainjection or in a targeted drug delivery system, such as a depot orsustained release formulation.

The pharmaceutical compositions of the present invention may bemanufactured by any of the methods well-known in the art, such as byconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping, or lyophilizing processes. Asnoted above, the compositions of the present invention can include oneor more physiologically acceptable carriers such as excipients andauxiliaries that facilitate processing of active molecules intopreparations for pharmaceutical use.

Proper formulation is dependent upon the route of administration chosen.For injection, for example, the composition may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal or nasal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. In a preferred embodiment of the presentinvention, the present compounds are prepared in a formulation intendedfor oral administration. For oral administration, the compounds can beformulated readily by combining the active compounds withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the compounds of the invention to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a subject. The compoundsmay also be formulated in rectal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa butter or other glycerides.

Pharmaceutical preparations for oral use can be obtained as solidexcipients, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate. Also, wetting agents such as sodium dodecyl sulfate may beincluded.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations for oral administration include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In one embodiment, the compounds of the present invention can beadministered transdermally, such as through a skin patch, or topically.In one aspect, the transdermal or topical formulations of the presentinvention can additionally comprise one or multiple penetrationenhancers or other effectors, including agents that enhance migration ofthe delivered compound. Transdermal or topical administration could bepreferred, for example, in situations in which location specificdelivery is desired.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, orany other suitable gas. In the case of a pressurized aerosol, theappropriate dosage unit may be determined by providing a valve todeliver a metered amount. Capsules and cartridges of, for example,gelatin, for use in an inhaler or insufflator may be formulated. Thesetypically contain a powder mix of the compound and a suitable powderbase such as lactose or starch.

Compositions formulated for parenteral administration by injection,e.g., by bolus injection or continuous infusion can be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Formulations for parenteral administration include aqueoussolutions or other compositions in water-soluble form.

Suspensions of the active compounds may also be prepared as appropriateoily injection suspensions. Suitable lipophilic solvents or vehiclesinclude fatty oils such as sesame oil and synthetic fatty acid esters,such as ethyl oleate or triglycerides, or liposomes. Aqueous injectionsuspensions may contain substances that increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

As mentioned above, the compositions of the present invention may alsobe formulated as a depot preparation. Such long acting formulations maybe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thepresent compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Suitable carriers for the hydrophobic molecules of the invention arewell known in the art and include co-solvent systems comprising, forexample, benzyl alcohol, a nonpolar surfactant, a water-miscible organicpolymer, and an aqueous phase. The co-solvent system may be the VPDco-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol. The VPD co-solvent system(VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in watersolution. This co-solvent system is effective in dissolving hydrophobiccompounds and produces low toxicity upon systemic administration.Naturally, the proportions of a co-solvent system may be variedconsiderably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied. For example, other low-toxicity nonpolar surfactants maybe used instead of polysorbate 80, the fraction size of polyethyleneglycol may be varied, other biocompatible polymers may replacepolyethylene glycol, e.g., polyvinyl pyrrolidone, and other sugars orpolysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic molecules may beemployed. Liposomes and emulsions are well known examples of deliveryvehicles or carriers for hydrophobic drugs. Liposomal delivery systemsare discussed above in the context of gene-delivery systems. Certainorganic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using sustained-release systems, such assemi-permeable matrices of solid hydrophobic polymers containing theeffective amount of the composition to be administered. Varioussustained-release materials are established and available to those ofskill in the art. Sustained-release capsules may, depending on theirchemical nature, release the compounds for a few weeks up to over 100days. Depending on the chemical nature and the biological stability ofthe therapeutic reagent, additional strategies for stabilization may beemployed.

For any composition used in the present methods of treatment, atherapeutically effective dose can be estimated initially using avariety of techniques well known in the art. For example, in a cellculture assay, a dose can be formulated in animal models to achieve acirculating concentration range that includes the IC₅₀ as determined incell culture. Dosage ranges appropriate for human subjects can bedetermined, for example, using data obtained from cell culture assaysand other animal studies.

A therapeutically effective dose of an agent refers to that amount ofthe agent that results in amelioration of symptoms or a prolongation ofsurvival in a subject. Toxicity and therapeutic efficacy of suchmolecules can be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., by determining the LD₅₀(the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratio oftoxic to therapeutic effects is the therapeutic index, which can beexpressed as the ratio LD₅₀/ED₅₀. Agents that exhibit high therapeuticindices are preferred.

Dosages preferably fall within a range of circulating concentrationsthat includes the ED₅₀ with little or no toxicity. Dosages may varywithin this range depending upon the dosage form employed and the routeof administration utilized. The exact formulation, route ofadministration, and dosage should be chosen, according to methods knownin the art, in view of the specifics of a subject's condition.

The amount of agent or composition administered will, of course, bedependent on a variety of factors, including the sex, age, and weight ofthe subject being treated, the severity of the affliction, the manner ofadministration, and the judgment of the prescribing physician.

The present compositions may, if desired, be presented in a pack ordispenser device containing one or more unit dosage forms containing theactive ingredient. Such a pack or device may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.Compositions comprising a compound of the invention formulated in acompatible pharmaceutical carrier may also be prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein,and are specifically contemplated.

EXAMPLES

The invention is further understood by reference to the followingexamples, which are intended to be purely exemplary of the invention.The present invention is not limited in scope by the exemplifiedembodiments, which are intended as illustrations of single aspects ofthe invention only. Any methods that are functionally equivalent arewithin the scope of the invention. Various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications fall within the scope of the appended claims.

Example 1 Synthesis of compound 2-methyl-1-(8-phenyl-octyl)-pyridiniumbromide

(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 2-picoline(3 mmol) in acetonitrile, and the solution mixture was refluxed for 24hours. The acetonitrile was removed in a vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no picoline was left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (70%).¹HNMR (300 MHz, CDCl3, ppm) 9.74 (d, 1H), 8.35 (m, 1H), 7.96 (m, 1H),7.86 (d, 1H), 7.15-7.25 (m, 4H), 4.92 (t, 2H), 2.95 (s, 3H), 1.88-1.98(m, 2H), 1.54-1.64 (m, 2H), 1.39-1.49 (m, 2H), 1.25-1.38 (br, 6H).

Example 2 Synthesis of Compound 3-methyl-1-(8-phenyl-octyl)-pyridiniumbromide

(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 3-picoline(3 mmol) in acetonitrile, and the solution refluxed for 24 hours. Theacetonitrile was removed in a vacuum and the resulting residue waspartitioned between ether and water. The aqueous layer was washedextensively with ether until no picoline was left in the aqueous layer.The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (76%).¹HNMR (300 MHz, CDCl3, ppm) 9.40 (s, 1H), 9.22 (d, 1H), 8.02 (d, 1H),7.96 (dd, 1H), 7.12-7.22 (dd, 4H), 4.94 (t, 2H), 2.62 (s, 3H), 2.56 (t,2H), 1.94-2.04 (m, 2H), 1.50-1.60 (m, 2H), 1.20-1.40 (br, 8H). ¹³CNMR,145.68, 144.65, 142.87, 142.37, 139.79, 128.55, 128.40, 127.89, 125.76,62.20, 36.19, 32.29, 31.73, 29.53, 29.44, 29.33, 26.40, 19.11.

Example 3 Synthesis of Compound2,4-dimethyl-1-(8-phenyl-octyl)-pyridinium bromide

(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 2,4-lutidine(3 mmol) in acetonitrile, and the solution refluxed for 24 hours. Theacetonitrile was removed in a vacuum and the resulting residue waspartitioned between ether and water. The aqueous layer was washedextensively with ether until no 2,4-lutidine was left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (70%).¹HNMR (300 MHz, CDCl3, ppm), 9.50 (d, 1H), 7.70 (d, 1H), 7.60 (s, 1H),7.10-7.30 (dd, 1H), 4.78 (t, 2H), 2.84 (s, 3H), 2.54-2.60 (m, 5H),1.80-1.92 (m, 2H), 1.50-1.60 (br, 2H), 1.20-1.45 (br, 6H).

Example 4 Synthesis of Compound 4-methyl-1-(8-phenyl-octyl)-pyridiniumbromide

(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 4-picoline(3 mmol) in acetonitrile, and the solution was refluxed for 24 hours.The acetonitrile was removed in vacuum and the resulting residue waspartitioned between ether and water. The aqueous layer was washedextensively with ether until no picoline was left in the aqueous layer.The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (78%).¹HNMR (300 MHz, CDCl3, ppm) 9.26 (d, 2H), 7.84 (d, 2H), 7.14-7.28 (dd,4H), 4.90 (t, 2H), 2.62 (s, 3H), 2.56 (t, 2H), 1.92-2.02 (m, 2H),1.50-1.60 (m, 2H), 1.20-1.40 (br, 8H). ¹³CNMR, 158.92, 144.28, 142.86,128.95, 128.56, 128.40, 125.76, 61.61, 36.19, 32.15, 31.71, 29.53,29.42, 29.31, 26.37, 22.63.

Example 5 Synthesis of Compound 1-dodec-7-ynyl-2-methyl-pyridiniumiodide

12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol)and 2-picoline (3 mmol) in butanone. room temperature. The butanone wasremoved in a vacuum, and the resulting residue was partitioned betweenwater and ethyl ether. The aqueous layer was washed extensively withether until no 2-picoline was left in the aqueous layer. The resultingaqueous solution of the product was extracted with chloroform. Thechloroform was removed to afford the product (85%). ¹HNMR (300 MHz,CDCl3, ppm) 9.62 (d, 1H), 8.39 (dd, 1H), 7.99 (m, 1H), 7.91 (d, 1H),4.88 (t, 2H), 2.97 (s, 3H), 2.12-2.20 m, 4H), 1.90-2.00 (m, 2H),1.32-1.58 (m, 8H), 0.88 (t, 3H).

Example 6 Synthesis of Compound 1-dodec-7-ynyl-3-methyl-pyridiniumiodide

12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol)and 3-picoline (3 mmol) in butanone. The mixture was refluxed for 3 daysand cooled to room temperature, filtrated. The butanone was removed in avacuum, and the resulting residue was partitioned between water andethyl ether. The aqueous layer was washed extensively with ether untilno 3-picoline was left in the aqueous layer. The resulting aqueoussolution of the product was extracted with chloroform. The chloroformwas removed to afford the product (82%). ¹HNMR (300 MHz, CDCl3, ppm)9.36 (s, 1H), 9.18 (d, 1H), 8.24 (d, 1H), 8.00 (dd, 1H), 4.92 (t, 2H),2.62 (s, 3H), 1.95-2.18 (m, 6H), 1.15-1.25 (br, 10H), 0.90 (t, 3H);¹³CNMR, 145.51, 144.12, 144.78, 139.46, 127.56, 80.44, 79.42, 61.75,31.72, 31.16, 28.65, 28.04, 25.52, 21.92, 18.75, 18.55, 18.40, 13.63.

Example 7 Synthesis of compound 1-dodec-7-ynyl-4-methyl-pyridiniumiodide

12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol)and 4-picoline (3 mmol) in butanone. The mixture was refluxed for 3 daysand cooled to room temperature, filtrated. The butanone was removed in avacuum, and the resulting residue was partitioned between water andethyl ether. The aqueous layer was washed extensively with ether untilno 4-picoline was left in the aqueous layer. The resulting aqueoussolution of the product was extracted with chloroform. The chloroformwas removed to afford the product (87%). ¹HNMR (300 MHz, CDCl3, ppm),9.28 (d, 2H), 7.92 (d, 2H), 4.92 (t, 2H), 2.68 (s, 3H), 1.96-2.18 (m,6H), 1.32-1.50 (br, 10H), 0.88 (t, 3H).

Example 8 Synthesis of Compound 1-dodec-7-ynyl-2,4-dimethyl-pyridiniumiodide

12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol)and 2,4-lutidine (3 mmol) in butanone. The mixture was refluxed for 3days and cooled to room temperature, filtrated. The butanone was removedin a vacuum, and the resulting residue was partitioned between water andethyl ether. The aqueous layer was washed extensively with ether untilno 2,4-lutidine was left in the aqueous layer. The resulting aqueoussolution of the product was extracted with chloroform. The chloroformwas removed to afford the product (84%). ¹HNMR (300 MHz, CDCl3, ppm),9.40 (d, 1H), 7.75 (d, 1H), 7.66 (s, 1H), 4.78 (t, 3H), 2.88 (s, 3H),2.60 (s, 3H), 2.05-2.15 (br, 4H), 1.80-2.00 (br, 2H), 1.30-1.50 (br,10H), 0.86 (t, 3H); ¹³CNMR, 156.73, 153.05, 145.84, 136.61, 127.27,80.86, 79.85, 58.12, 31.54, 30.94, 39.09, 26.17, 22.39, 22.30, 21.03,18.96, 18.79, 14.02.

Example 9 Synthesis of Compound 1-dodec-7-ynyl-3,5-dimethyl-pyridiniumiodide

12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol)and 3,5-lutidine (3 mmol) in butanone. The mixture was refluxed for 3days and cooled to room temperature, filtrated. The butanone was removedin vacuum, and the resulting residue was partitioned between water andethyl ether. The aqueous layer was washed extensively with ether untilno 3,5-lutidine was left in the aqueous layer. The resulting aqueoussolution of the product was extracted with chloroform. The chloroformwas removed to afford the product (78%). ¹HNMR (300 MHz, CDCl3, ppm),9.06 (s, 2H), 8.00 (s, 1H), 4.86 (t, 3H), 2.48 (s, 3H), 1.98-2.16 (m,6H), 1.32-1.48 (br, 10H), 0.88 (t, 3H); ¹³CNMR, 146.12, 141.38, 138.64,80.43, 79.53, 61.46, 31.70, 31.17, 28.68, 28.07, 25.55, 21.92, 18.57,18.42, 13.63.

Example 10 Synthesis of Compound 1-dodec-7-ynyl-3,4-dimethyl-pyridiniumiodide

12-Chloro-dodec-5-yne (1 mmol) was mixed with Sodium iodide (3 mmol) and3,4-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 daysand cooled to room temperature, filtrated. The butanone was removed invacuum, and the resulting residue was partitioned between water andethyl ether. The aqueous layer was washed extensively with ether untilno 3,4-lutidine was left in the aqueous layer. The resulting aqueoussolution of the product was extracted with chloroform. The chloroformwas removed to afford the product (72%). ¹HNMR, (300 MHz, CDCl3, ppm,ppm), 9.22 (s, 1H), 9.04 (d, 1H), 7.80 (d, 1H), 4.84 (t, 3H), 2.52 (s,3H), 2.50 (s, 3H), 1.92-2.14 (m, 6H), 1.28-1.45 (m, 10H), 0.84 (t, 3H).¹³CNMR, 157.84, 143.39, 141.81, 138.53, 128.72, 80.80, 79.90, 61.23,32.03, 31.54, 29.08, 28.48, 25.91, 22.30, 20.78, 18.96, 18.79, 17.44,14.02.

Example 11 Synthesis of 1-dodec-9-ynyl-2-methyl-pyridinium bromide

12-Bromo-dodec-3-yne (1 mmol) was added to a solution of 2-picoline (3mmol) in acetonitrile, and the solution was refluxed for 24 hours. Theacetonitrile was removed in vacuum, and the resulting residue waspartitioned between ether and water. The aqueous layer was washedextensively with ether until no 2-picoline was left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (70%).¹HNMR (300 MHz, CDCl3, ppm), 9.68 (d, 1H), 8.28 (m, 1H), 7.96 (m, 1H),7.84 (d, 1H), 4.94 (t, 2H), 2.98 (s, 3H), 2.05-2.20 (m, 4H), 1.88-2.00(m, 2H), 1.20-1.60 (br, 10H), 1.10 (t, 3H).

Example 12 Synthesis of Compound 1-dodec-9-ynyl-3-methyl-pyridiniumbromide

12-Bromo-dodec-3-yne (1 mmol) was added to a solution of 3-picoline (3mmol) in acetonitrile, and the solution was refluxed for 24 hours. Theacetonitrile was removed in a vacuum, and the resulting residue waspartitioned between ether and water. The aqueous layer was washedextensively with ether until no picoline was left in the aqueous layer.The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (70%).¹HNMR (300 MHz, CDCl3, ppm), 9.42 (s, 1H), 9.24 (d, 1H), 8.24 (d, 1H),8.00 (dd, 1H), 4.95 (t, 2H), 2.62 (s, 3H), 1.95-2.2 (m, 6H), 1.23-1.45(br, 10H), 1.1 (t, 3H); ¹³CNMR, 145.29, 144.24, 141.98, 139.42, 127.51,81.57, 79.26, 61.83, 31.90, 28.95, 28.92, 28.82, 28.62, 26.02, 18.72,18.63, 14.38, 12.40.

Example 13 Synthesis of Compound 1-dodec-9-ynyl-4-methyl-pyridiniumbromide

12-Bromo-dodec-3-yne (1 mmol) was added to a solution of 4-picoline (3mmol) in acetonitrile, and the solution was refluxed for 24 hours. Theacetonitrile was removed in a vacuum, and the resulting residue waspartitioned between ether and water. The aqueous layer was washedextensively with ether until no picoline was left in the aqueous layer.The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (82%).¹HNMR (300 MHz, CDCl₃, ppm), 9.24 (d, 2H), 7.86 (d, 2H), 4.90 (t, 2H),2.64 (s, 3H), 1.95-2.16 (m, 6H), 1.26-1.34 (br, 10H), 0.88 (t, 3H).

Example 14 Synthesis of 1-[4-(4-butyl-phenyl)-butyl]-2-methyl-pyridiniumbromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of2-picoline (3 mmol) in acetonitrile, and the solution was refluxed for24 hours. The acetonitrile was removed in a vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no 2-picoline was left in theaqueous layer. The resulting aqueous solution of the product wasextracted with chloroform. The chloroform was removed to afford theproduct (74%). ¹HNMR (300 MHz, CDCl3, ppm), 9.69 (d, J=6.6, 1H),8.25-8.30 (m, 1H), 7.90-7.95 (m, 1H), 7.77 (d, J=7.8, 1H), 7.04-7.10 (m,4H), 4.92 (t, 7.5, 2H), 2.84 (s, 3H), 2.66 (t, J=7.2, 2H), 2.56 (t,J=7.5, 2H), 1.89-1.98 (m, 2H), 1.78-1.86 (m, 2H), 1.51-1.59 (m, 2H),1.27-1.37 (m, 2H), 0.91 (t, J=7.2, 3H).

Example 15 Synthesis of Compound1-[4-(4-butyl-phenyl)-butyl]-3-methyl-pyridinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of3-picoline (3 mmol) in acetonitrile and the solution refluxed for 24hours. The acetonitrile was removed in vacuum, and the resulting residuewas partitioned between ether and water. The aqueous layer was washedextensively with ether until no picoline was left in the aqueous layer.The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (75%).¹HNMR (300 MHz, CDCl3, ppm), 9.32 (s, 1H), 9.2 (d, J=5.1, 1H), 8.16 (d,J=5.1, 7.91 (m, 1H), 7.07 (d, J=8.4, 2H), 7.02 (d, J=8.4, 2H), 4.96 (t,J=7.2, 2H), 2.52-2.64 (m, 7H), 2.00-2.06 (m, 2H), 1.60-1.70 (m, 2H),1.60-1.60 (m, 2H), 1.29-1.36 (m, 2H), 0.90 (t, J=7.2, 3H); ¹³CNMR,145.62, 144.71, 142.37, 140.84, 139.73, 138.32, 128.66, 128.48, 127.78,61.82, 35.54, 34.95, 34.05, 31.71, 27.93, 22.72, 19.07, 14.33.

Example 16 Synthesis of Compound1-[4-(4-butyl-phenyl)-butyl]-4-methyl-pyridinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of4-picoline (3 mmol) in acetonitrile, and the solution was refluxed for24 hours. The acetonitrile was removed in a vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no picoline was left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (72%).¹HNMR (300 MHz, CDCl3, ppm), 9.22 (d, J=6.6, 2H), 7.79 (d, J=6.6, 2H),7.05 (d, J=8.4, 2H), 7.02 (d, J=8.4, 2H), 4.90 (t, J=7.5, 3H), 2.51-2.63(m, 7H), 1.96-2.06 (m, 2H), 1.58-1.68 (m, 2H), 1.51-1.61 (m, 2H),1.31-1.37 (m, 2H), 0.89 (t, J=7.2, 3H); ¹³CNMR, 158.91, 144.31, 140.83,138.30, 128.92, 128.66, 128.45, 61.26, 35.54, 34.95, 34.04, 31.61,27.95, 22.73, 22.57, 14.33.

Example 17 Synthesis of2-[4-(4-butyl-phenyl)-butyl]-5,6,7,8-tetrahydro-isoquinolinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution oftetrahydroisoquinoline (2 mmol) in acetonitrile, and the solution wasrefluxed for 24 hours. The acetonitrile was removed in vacuum, and theresulting residue was partitioned between ether and water. The aqueouslayer was washed extensively with ether until no tetrahydroisoquinolinewas left in the aqueous layer. The resulting aqueous solution of theproduct was extracted with chloroform. The chloroform was removed toafford the product (72%). ¹HNMR (300 MHz, CDCl3, ppm), 9.12 (s, 1H),8.85 (d, J=6.0, 1H), 7.61 (d, J=6.0, 1H), 7.02-7.08 (m, 4H), 4.83 (t,7.5, 3H), 2.92-2.94 (m, 4H), 2.61 (t, J=7.5, 2H), 2.54 (t, J=7.5, 2H),1.90-2.04 (m, 2H), 1.80-1.90 (m, 4H), 1.62-1.69 (m, 2H), 1.53-1.62 (m,2H), 1.29-1.37 (m, 2H), 0.90 (t, J=7.2, 3H). ¹³CNMR, 157.94, 144.18,140.82, 140.64. 138.96, 138.37, 128.65, 128.48, 127.99, 61.16, 35.54,34.99, 34.05, 31.56, 29.92, 27.98, 26.69, 22.74, 21.37, 14.33.

Example 18 Synthesis of1-[4-(4-butyl-phenyl)-butyl]-3-(3-hydroxy-propyl)-pyridinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution ofhydroxypropanylpyridine (2 mmol) in acetonitrile, and the solution wasrefluxed for 24 hours. The acetonitrile was removed in a vacuum, and theresulting residue was partitioned between ether and water. The aqueouslayer was washed extensively with ether until no hydroxypropanylpyridinewas left in the aqueous layer. The resulting aqueous solution of theproduct was extracted with chloroform. The chloroform was removed toafford the product (65%). ¹HNMR (300 MHz, CDCl3, ppm), 9.41 (s, 1H),8.85 (d, J=6.3, 1H), 8.26 (d, J=8.1, 1H), 7.89 (dd, J=6.3, J=8.1, 1H),7.02-7.07 (m, 4H), 4.90 (t, J=7.5, 2H), 3.59 (t, J=5.4, 2H), 3.00 (t,J=6.9, 2H), 2.62 (t, J=7.2, 2H), 2.55 (t, J=7.8, 2H), 1.95-2.05 (m, 4H),1.57-1.69 (m, 2H), 1.50-1.60 (m, 2H), 1.29-1.37 (m, 2H), 0.90 (t, J=7.2,3H).

Example 19 Synthesis of Compound1-[4-(4-butyl-phenyl)-butyl]-2,4-dimethyl-pyridinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of2,4-lutidine (3 mmol) in acetonitrile, and the solution was refluxed for24 hours. The acetonitrile was removed in a vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no lutidine left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (79%).¹HNMR (300 MHz, CDCl3, ppm), 9.51 (d, J=6.2, 1H), 7.67 (d, J=6.2, 1H),7.54 (s, 1H), 7.05-7.07 (m, 4H), 4.83 (t, J=7.2, 2H), 2.77 (s, 3H), 2.64(t, J=7.2, 2H), 2.52-2.58 (m, 5H), 1.87-1.92 (m, 2H), 1.76-1.82 (m, 2H),1.50-1.58 (m, 2H), 1.29-1.37 (m, 2H), 0.91 (t, J=7.8, 3H).

Example 20 Synthesis of1-[4-(4-butyl-phenyl)-butyl]-3,4-dimethyl-pyridinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of3,4-lutidine (3 mmol) in acetonitrile, and the solution was refluxed for24 hours. The acetonitrile was removed in a vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no lutidine left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (79%).1HNMR (300 MHz, CDCl3, ppm), 9.20 (s, 1H), 9.03 (d, J=6.3, 1H), 7.72 (d,J=6.3, 1H), 7.00-7.07 (m, 4H), 4.87 (t, J=7.5, 2H), 2.60 (t, J=7.8, 2H),2.54 (t, J=7.8, 2H), 2.49 (s, 3H), 2.46 (s, 3H), 1.99-2.04 (m, 2H),1.50-1.66 (m, 4H), 1.28-1.36 (m, 2H), 0.90 (t, J=7.5, 3H). ¹³CNMR157.60, 143.56, 141.92, 140.78, 138.40, 128.63, 128.57, 128.47, 61.00,35.54, 34.98, 34.04, 31.59, 27.96, 22.73, 20.66, 17.36, 14.31.

Example 21 Synthesis of1-[4-(4-butyl-phenyl)-butyl]-3,5-dimethyl-pyridinium bromide

1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of3,5-lutidine (3 mmol) in acetonitrile, and the solution was refluxed for24 hours. The acetonitrile was removed in a vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no lutidine was left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (81%).¹HNMR (300 MHz, CDCl3, ppm), 9.11 (s, 2H), 7.92 (s, 1H), 7.00-7.06 (m,4H), 4.88 (t, J=7.5, 2H), 2.51-2.62 (m, 7H), 1.99-2.05 (m, 2H),1.49-1.66 (m, 4H), 1.28-1.35 (m, 2H), 0.89 (t, J=7.2, 3H). ¹³CNMR,146.17, 141.96, 140.81, 138.91, 138.40, 128.63, 128.48, 61.60, 35.54,34.98, 34.05, 31.68, 27.95, 22.72, 18.88, 14.31.

Example 22 Synthesis of Compound1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-methyl-pyridinium bromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof 3-picoline (3 mmol) in acetonitrile, and the solution was refluxedfor 24 hours. The acetonitrile was removed in a vacuum, and theresulting residue was partitioned between ether and water. The aqueouslayer was washed extensively with ether until no picoline was left inthe aqueous layer. The resulting aqueous solution of the product wasextracted with chloroform. The chloroform was removed to afford theproduct (77%). ¹HNMR R (300 MHz, CDCl3, ppm), 9.48 (s, 1H), 9.33 (d,J=6.6, 1H), 8.24 (d, J=7.2, 1H), 7.93 (dd, J=6.6, J=7.2, 1H), 7.16 (d,J=8.2, 2H), 7.06 (d, J=8.2, 2H), 5.21 (t, J=6.0, 2H), 3.26 (t, J=6.0,2H), 2.59 (s, 3H), 2.56 (t, 2H), 1.49-1.59 (m 2H), 1.25-1.37 (m, 2H),0.9 (t, J=7.2, 3H); ¹³CNMR, 145.70, 144.78, 143.64, 142.26, 138.98,131.15, 128.32, 126.94, 118.92, 85.84, 82.45, 59.90, 35.45, 33.28,22.81. 22.24, 18.71, 13.89.

Example 23 Synthesis of Compound1-[4-(4-butyl-phenyl)-but-3-ynyl]-4-methyl-pyridinium bromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof 4-picoline (3 mmol) in acetonitrile, and the solution was refluxedfor 24 hours. The acetonitrile was removed in vacuum, and the resultingresidue was partitioned between ether and water. The aqueous layer waswashed extensively with ether until no picoline was left in the aqueouslayer. The resulting aqueous solution of the product was extracted withchloroform. The chloroform was removed to afford the product (67%).¹HNMR (300 MHz, CDCl3, ppm), 9.40 (d, J=6.9, 1H), 7.80 (d, 1H), 7.17 (d,J=7.8, 2H), 7.06 (d, J=7.8, 2H), 5.2 (t, 2H), 3.23 (t, 2H), 2.65 (s,3H), 2.56 (t, J=7.8, 2H), 1.49-1.57 (m, 2H), 1.27-1.35 (m, 2H), 0.90 (t,J=7.5, 3H).

Example 24 Synthesis of1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-ethyl-pyridinium bromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof 3-ethylpyridine (3 mmol) in acetonitrile, and the solution wasrefluxed for 24 hours. The acetonitrile was removed in vacuum, and theresulting residue was partitioned between ether and water. The aqueouslayer was washed extensively with ether until no ethylpyridine was leftin the aqueous layer. The resulting aqueous solution of the product wasextracted with chloroform. The chloroform was removed to afford theproduct (67%). ¹HNMR (300 MHz, CDCl3, ppm), 9.43 (d, J=6.0, 1H), 9.41(s, 1H), 8.25 (d, J=8.1, 1H), 7.96 (dd, J=6.0, J=8.1, 1H), 7.15 (d,J=8.1, 2H), 7.06, d, J=8.1, 2H), 5.26 (t, J=6.0, 2H), 3.26 (t, J=6.0,2H), 2.90 (q, J=7.5, 2H), 2.56 (t, J=8.1, 2H), 1.49-1.59 (m, 2H),1.27-1.37 (m, 5H), 0.90 (t, J=7.2, 3H); ¹³CNMR, 144.65, 144.46, 144.14,143.65, 142.45, 131.14, 128.30, 127.12, 118.87, 85.88, 82.45, 59.99,35.45, 33.27, 26.01, 22.85, 22.21, 14.26, 13.88.

Example 25 Synthesis of2-[4-(4-butyl-phenyl)-but-3-ynyl]-5,6,7,8-tetrahydro-isoquinoliniumbromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof tetrahyroisoquinoline (2 mmol) in acetonitrile, and the solution wasrefluxed for 24 hours. The acetonitrile was removed in a vacuum, and theresulting residue was partitioned between ether and water. The aqueouslayer was washed extensively with ether until no tetrahyroisoquinolinewas left in the aqueous layer. The resulting aqueous solution of theproduct was extracted with chloroform. The chloroform was removed toafford the product (68%). ¹HNMR (300 MHz, CDCl3, ppm), 9.30 (s, 1H),9.04 (d, J=6.3, 2H), 7.62 (d, J=6.3, 1H), 7.18 (d, J=8.4, 2H), 7.06 (d,J=8.4, 2H), 5.10 (t, J=6.0, 3.21 (t, J=6.0, 2H), 2.94-2.96 (m, 2H), 2.56(t, J=8.1, 2H), 1.81-1.87 (m, 2H), 1.49-1.56 (m, 2H), 1.27-1.34 (m, 2H),0.89 (t, J=7.2, 3H); ¹³CNMR, 158.51, 144.59, 143.95, 140.93, 138.61,131.55, 128.71, 127.57, 119.46, 85.97, 83.23, 59.58, 35.86, 33.69,31.01, 26.70, 23.12, 22.63, 21.37, 14.28.

Example 26 Synthesis of1-[4-(4-butyl-phenyl)-but-3-ynyl]-3,4-dimethyl-pyridinium bromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof 3-hydroypropanylpyridine (2 mmol) in acetonitrile, and the solutionwas refluxed for 24 hours. The acetonitrile was removed in a vacuum, andthe resulting residue was partitioned between ether and water. Theaqueous layer was washed extensively with ether until nohydroypropanylpyridine was left in the aqueous layer. The resultingaqueous solution of the product was extracted with chloroform. Thechloroform was removed to afford the product (60%). ¹HNMR (300 MHz,CDCl₃, ppm), 9.39 (s, 1H), 9.13 (d, J=6.3, 1H), 7.70 (d, J=6.3, 1H),7.17 (d, J=8.1, 2H), 7.07 (d, J=8.1, 2H), 5.13 (t, J=6.0, 2H), 3.23 (t,J=6.0, 2H), 2.57 (t, J=7.8, 2H), 2.53 (s, 3H), 2.48 (s, 3H), 1.50-1.58(m, 2H), 1.28-1.37 (m, 2H), 0.90 (t, J=7.2, 3H); ¹³CNMR, 158.19, 143.98,138.11, 131.53, 128.69, 128.05, 119.45, 83.11, 59.60, 35.84, 33.64,23.12, 22.62, 20.77, 17.35, 14.23.

Example 27 Synthesis of1-[4-(4-butyl-phenyl)-but-3-ynyl]-3,5-dimethyl-pyridinium bromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof 3,5-lutidine (2 mmol) in acetonitrile, and the solution was refluxedfor 24 hours. The acetonitrile was removed in a vacuum, and theresulting residue was partitioned between ether and water. The aqueouslayer was washed extensively with ether until no lutidine was left inthe aqueous layer. The resulting aqueous solution of the product wasextracted with chloroform. The chloroform was removed to afford theproduct (80%). ¹HNMR (300 MHz, CDCl₃, ppm), 9.39 (s, 1H), 9.13 (d,J=6.3, 1H), 7.70 (d, J=6.3, 1H), 7.17 (d, J=8.1, 2H), 7.07 (d, J=8.1,2H), 5.13 (t, J=6.0, 2H), 3.23 (t, J=6.0, 2H), 2.57 (t, J=7.8, 2H), 2.53(s, 3H), 2.48 (s, 3H), 1.50-1.58 (m, 2H), 1.28-1.37 (m, 2H), 0.90 (t,J=7.2, 3H); ¹³CNMR, 158.19, 143.98, 138.11, 131.53, 128.69, 128.05,119.45, 83.11, 59.60, 35.84, 33.64, 23.12, 22.62, 20.77, 17.35, 14.23.

Example 28 Synthesis of1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-(3-hydroxy-propyl)-pyridiniumbromide

1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solutionof 3-hydroypropanylpyridine (2 mmol) in acetonitrile, and the solutionwas refluxed for 24 hours. The acetonitrile was removed in vacuum, andthe resulting residue was partitioned between ether and water. Theaqueous layer was washed extensively with ether until nohydroypropanylpyridine was left in the aqueous layer. The resultingaqueous solution of the product was extracted with chloroform. Thechloroform was removed to afford the product (60%). ¹HNMR (300 MHz,CDCl3, ppm), 9.46 (s, 1H), 9.04 (d, J=6.0, 1H), 8.33 (d, J=8.1, 1H),7.92 (dd, J=6.0, J=8.1, 1H), 7.16 (d, J=8.4, 2H), 7.04 (d, J=8.1, 2H),5.12 (t, J=6.6, 2H), 3.57 (t, 6.0, 2H), 3.22 (t, J=6.0, 2H), 2.98 (t,J=7.2, 2H), 2.54 (t, J=7.5, 3H), 1.94 (p, 6.0, 2H), 1.47-1.57 (m, 2H),1.26-1.34 (m, 2H), 0.89 (t, J=7.5, 3H); ¹³CNMR, 145.54, 144.99, 143.62,141.83, 131.20, 128.32, 126.94, 118.95, 85.65, 82.43, 59.92, 59.78,58.26, 35.44, 33.28, 32.33, 29.24, 22.68, 22.23, 18.39, 13.88.

Example 29 Synthesis of compound3-methyl-1-(13-pyridin-3-yl-tridecyl)-pyridinium bromide

3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to 3-picoline (5 ml),and the mixture was heated at 50 C overnight. The excess picoline wasremoved in vacuum, and the resulting residue was partitioned betweenwater and ether. The aqueous layer was washed extensively with etheruntil no picoline left in the aqueous layer, and then the aqueous layerwas extracted with chloroform. The chloroform was removed to afford theproduct (65%). ¹HNMR (300 MHz, CDCl3, ppm), 9.36 (s, 1H), 9.22 (d,J=5.4, 1H), 8.44 (br, 2H), 8.21 (d, J=7.5, 1H), 7.97 (m, 1H), 7.54 (d,7.2, 1H), 7.24-7.24 m, 1H), 4.96 (t, J=7.2, 2H), 2.58-2.65 M, 5H),2.00-2.07 (m, 4H), 1.58-1.60 (m, 2H), 1.20-1.36 (m, 16H); ¹³CNMR,148.76, 146.10, 145.58, 144.77, 142.38, 139.83, 137.29, 127.80, 123.98,62.28, 58.71, 33.31, 32.36, 31.32, 29.80, 29.74, 29.64, 29.38, 29.35,26.45, 19.15, 18.81.

Example 30 Synthesis of Compound3,4-dimethyl-1-(13-pyridin-3-yl-tridecyl)-pyridinium bromide

3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to 3,4-lutidine (5ml), and the mixture was heated at 50 C overnight. The excess picolinewas removed in a vacuum, and the resulting residue was partitionedbetween water and ether. The aqueous layer was washed extensively withether until no 3,4-lutidine was left in the aqueous layer, and then theaqueous layer was extracted with chloroform. The chloroform was removedto afford the product (60%). ¹HNMR (300 MHz, CDCl3, ppm), 9.23 (s, 1H),9.04 (d, J=6.3, 1H), 8.40 (br, 2H), 7.79 (d, J=6.0, 1H), 7.48 (d, 8.1,1H), 7.18-7.20 (m, 1H), 4.83 (t, J=7.5, 2H), 2.58 (t, J=7.5, 2H), 2.52(s, 3H), 2.49 (s, 3H), 2.21 (br, 1H), 1.82-2.02 (m, 2H), 1.54-1.62 (m,2H), 1.15-1.35 (br, 12H). ¹³CNMR, 157.61, 149.68, 146.92, 143.35,141.91, 138.45, 138.33, 136.32, 128.65, 123.57, 61.37, 33.31, 32.19,31.41, 29.85, 29.80, 29.68, 29.41, 26.45, 20.69, 17.40.

Example 31 Synthesis of Compound3,5-dimethyl-1-(13-pyridin-3-yl-tridecyl)-pyridinium bromide

3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to 3,5-lutidine (5ml), and the mixture was heated at 50 C overnight. The excess picolinewas removed in a vacuum, and the resulting residue was partitionedbetween water and ether. The aqueous layer was washed extensively withether until no 3,5-lutidine was left in the aqueous layer, and then theaqueous layer was extracted with chloroform. The chloroform was removedto afford the product (62%). ¹HNMR (300 MHz, CDCl3, ppm), 9.10 (s, 2H),8.45 (br, 2H), 7.96 (s, 1H), 7.57 (d, J=7.5, 1H), 7.24-7.27 (m, 1H),4.89 (t, J=7.5, 2H), 2.59-2.54 (m, 8H), 1.99-2.04 (m, 2H), 1.57-1.62 (m,2H), 1.21-1.38 (m, 18H), ¹³CNMR, 148.07, 146.11, 145.45, 141.94, 139.01,137.96, 124.16, 62.13, 58.74, 33.29, 32.34, 31.26, 29.76, 29.73, 29.62,29.39, 29.30, 26.49, 18.98, 18.82.

Example 32 Synthesis of Compound2-(13-pyridin-3-yl-tridecyl)-5,6,7,8-tetrahydro-isoquinolinium bromide

3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to5,6,7,8-tetrahydro-isoquinoline (5 ml), and the mixture was heated at 50C overnight. The resulting residue was treated with ether, and the etherwas decanted after deposition for 30′. The residue was partitionedbetween water and ether. The aqueous layer was washed extensively withether, and then the aqueous layer was extracted with chloroform. Thechloroform was removed to afford the product (62%). ¹HNMR (300 MHz,CDCl3, ppm), 9.22 (s, 1H), 8.90 (d, J=6.3, 1H), 8.44 (br, 2H), 7.67 (d,J=6.3, 1H), 7.55 (d, 8.1, 7.24-7.28 (m, 1H), 4.83 (t, J=7.2, 2.98-3.01(m, 4H), 2.60 (t, J=7.8, 2H), 1.94-2.02 (m, 2H), 1.87-1.90 (m, 4H),1.56-1.60 (m, 2H), 1.19-1.35 (br, 20H); ¹³CNMR, 157.87, 148.79, 146.13,144.20, 140.68, 138.95, 138.80, 137.26, 128.08, 123.92, 61.40, 58.62,33.30, 32.20, 31.34, 29.94, 29.82, 29.77, 29.67, 29.42, 29.36, 26.71,26.46, 21.40, 18.81.

Example 33 Synthesis of Compound 5-(1,1′-biphenyl-4-yl)-pent-4-yn-1-ol

4-Bromobiphenyl (10.28 g, 44.10 mmol), 4-pentyn-1-ol (4.45 g, 52.92mmol), and bis(triphenylphosphine)palladium(II) dichloride (310 mg, 0.44mmol) were stirred in triethylamine (100 mL) under nitrogen for 5 min.Copper(I) iodide (42 mg, 0.22 mmol) was added, and the mixture wasstirred for 4 hrs at 65° C. The mixture was cooled to room temperatureand filtered through a celite pad, rinsed with ethylacetate. Thecombined filtrate was evaporated to dryness under reduced pressure. Theresulting residue was purified by column chromatography(hexanes:ethylacetate 3:2) to afford 7.78 g of the title compound.Yield: 75%. ¹H NMR (300 MHz, CDCl₃) δ 1.88 (m, 2H), 2.57 (t, J=6.9 Hz,2H), 3.84 (t, J=6.0 Hz, 2H), 7.32-7.60 (m, 9H) ppm; ¹³C NMR (75 MHz,CDCl₃) δ 16.4, 31.7, 62.1, 81.2, 90.2, 122.8, 127.0, 127.1, 127.6,128.9, 132.0, 140.1 ppm.

Example 34 Synthesis of Compound 4-(5-bromo-pent-1-ynl)-1,1′-biphenyl

5-(1,1′-biphenyl-4-yl)-4-pentyn-1-ol (3.40 g, 14.39 mmol) and carbontetrabromide (6.21 g, 18.71 mmol) were dissolved in dry methylenechloride (20 mL) and cooled to 0° C. Triphenyl phosphine (5.15 g, 19.65mmol) in methylene chloride (10 mL) was added dropwise, and the mixturewas stirred for 1 h at 0° C. The mixture was poured into hexanes (100mL), and then filtered through a short silica gel column, washed withethylacetate/hexanes (1/4). The combined organic solvents wereevaporated to dryness under reduced pressure. The resulting residue waspurified by column chromatography (hexanes:ethylacetate 30:1) to afford4.20 g of the title compound. Yield: 97%. ¹H NMR (300 MHz, CDCl₃) δ 2.15(m, 2H), 2.63 (t, J=6.9 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 7.32-7.60 (m,9H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 18.5, 31.8, 32.8, 81.7, 88.8, 122.6,127.0, 127.1, 127.6, 128.9, 132.1, 140.5, 140.6 ppm.

Example 35 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-2-methyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (357 mg, 1.19 mmol) and2-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 393 mg of the titlecompound. Yield: 84%. ¹H NMR (300 MHz, CDCl₃) δ 2.31 (m, 2H), 2.75 (t,J=6.3 Hz, 2H), 3.04 (s, 3H), 5.14 (t, J=7.8 Hz, 2H), 7.30-7.59 (m, 9H),7.94-8.01 (m, 2H), 8.38 (t, J=7.8 Hz, 1H), 9.82 (d, J=6.0 Hz, 1H) ppm;¹³C NMR (75 MHz, CDCl₃) δ 16.9, 21.1, 29.7, 57.2, 82.4, 88.1, 121.8,126.4, 127.0, 127.1, 127.7, 128.9, 130.3, 132.0, 140.1, 140.8, 145.3,146.8, 154.6 ppm.

Example 36 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-methyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (377 mg, 1.26 mmol) and3-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultingmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 433 mg of the titlecompound. Yield: 88%. ¹H NMR (300 MHz, CDCl₃) δ 2.43 (m, 2H), 2.58 (s,3H), 2.67 (t, J=6.6 Hz, 2H), 5.16 (t, J=6.9 Hz, 2H), 7.30-7.61 (m, 9H),7.98 (dd, J=8.1, 6.0 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 9.37 (d, J=6.0 Hz,1H), 9.50 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 16.8, 19.0, 30.5, 60.9,82.4, 88.0, 121.9, 126.9, 127.7, 127.8, 128.9, 132.0, 139.7, 140.1,140.7, 142.5, 144.8, 145.8 ppm.

Example 37 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-4-methyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (360 mg, 1.20 mmol) and4-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 435 mg of the titlecompound. Yield: 92%. ¹H NMR (300 MHz, CDCl₃) δ 2.40 (m, 2H), 2.49 (s,3H), 2.67 (t, J=6.6 Hz, 2H), 5.16 (t, J=6.9 Hz, 2H), 7.30-7.59 (m, 9H),7.80 (d, J=6.3 Hz, 2H), 9.43 (d, J=6.3 Hz, 2H) ppm; ¹³C NMR (75 MHz,CDCl₃) δ 16.8, 22.4, 30.3, 60.3, 82.3, 88.0, 121.9, 126.9, 127.0, 127.8,128.8, 129.0, 132.0, 140.1, 140.7, 144.5, 159.2 ppm.

Example 38 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-2,4-dimethyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (328 mg, 1.10 mmol) and2,4-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resultingmixture was washed with diethyl ether, and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 360 mg of the titlecompound. Yield: 81%. ¹H NMR (300 MHz, CDCl₃) δ 2.29 (m, 2H), 2.51 (s,3H), 2.73 (t, J=6.3 Hz, 2H), 2.96 (s, 3H), 5.04 (t, J=7.5 Hz, 2H),7.30-7.60 (m, 9H), 7.70 (s, 2H), 9.56 (d, J=7.2 Hz, 1H) ppm; ¹³C NMR (75MHz, CDCl₃) δ 16.8, 20.7, 22.1, 29.4, 56.4, 82.2, 88.1, 121.8, 126.9,127.0, 127.7, 128.9, 130.5, 131.9, 140.0, 140.7, 145.8, 153.3, 158.7ppm.

Example 39 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3,4-dimethyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (327 mg, 1.09 mmol) and3,4-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 380 mg of the titlecompound. Yield: 86%. ¹H NMR (300 MHz, CDCl₃) δ 2.36 (s, 3H), 2.43 (s,3H), 2.55 (m, 2H), 2.69 (t, J=6.6 Hz, 2H), 5.10 (t, J=6.6 Hz, 2H),7.28-7.59 (m, 9H), 7.77 (d, J=6.0 Hz, 1H), 9.22 (d, J=6.0 Hz, 1H), 9.38(s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 16.8, 17.2, 20.4, 30.2, 60.1,82.0, 88.2, 122.0, 126.9, 127.7, 128.5, 128.9, 131.9, 138.2, 140.0,140.6, 142.1, 143.7, 157.9 ppm.

Example 40 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3,5-dimethyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (360 mg, 1.20 mmol) and3,5-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 439 mg of the titlecompound. Yield: 90%. ¹H NMR (300 MHz, CDCl₃) δ 2.43 (m, 2H), 2.54 (s,6H), 2.67 (t, J=6.6 Hz, 2H), 5.10 (t, J=6.9 Hz, 2H), 7.30-7.60 (m, 9H),7.90 (s, 1H), 9.24 (s, 2H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 16.8, 18.8,30.4, 60.7, 82.3, 88.1, 122.0, 127.0, 127.8, 129.0, 132.0, 138.9, 140.1,140.8, 142.1, 146.4 ppm.

Example 41 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-quinolinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (329 mg, 1.10 mmol) andquinoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (30mL). The aqueous solution was extracted with ethyl acetate (30 mL×3).Water was removed by lyophilization to afford 328 mg of the titlecompound. Yield: 70%. ¹H NMR (300 MHz, CDCl₃) δ 2.49 (m, 2H), 2.84 (t,J=6.3 Hz, 2H), 5.67 (t, J=7.2 Hz, 2H), 7.22-7.62 (m, 9H), 7.93 (t, J=7.5Hz, 1H), 8.10-8.21 (m, 2H), 8.34 (d, J=7.5 Hz, 1H), 8.63 (d, J=9.0 Hz,1H), 9.11 (d, J=8.1 Hz, 1H), 10.60 (d, J=5.4 Hz, 1H) ppm; ¹³C NMR (75MHz, CDCl₃) δ 17.1, 29.1, 57.0, 82.2, 88.4, 118.4, 121.8, 122.5, 126.9,127.7, 128.9, 130.0, 130.2, 131.2, 131.9, 136.2, 137.8, 140.0, 140.7,147.5, 150.5 ppm.

Example 42 Synthesis of Compound2-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-isoquinolinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (325 mg, 1.09 mmol) andisoquinoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (30mL). The aqueous solution was extracted with ethyl acetate (30 mL×3).Water was removed by lyophilization to afford 340 mg of the titlecompound. Yield: 73%. ¹H NMR (300 MHz, CDCl₃) δ 2.51 (m, 2H), 2.72 (t,J=6.3 Hz, 2H), 5.34 (t, J=6.6 Hz, 2H), 7.16 (d, J=8.7 Hz, 1H), 7.30-7.57(m, 9H), 7.88 (m, 2H), 8.01 (d, J=3.9 Hz, 1H), 8.29 (d, J=6.6 Hz, 1H),8.69 (d, J=8.4 Hz, 1H), 8.87 (d, J=6.6 Hz, 1H), 11.14 (s, 1H) ppm; ¹³CNMR (75 MHz, CDCl₃) δ 16.9, 30.2, 60.8, 82.3, 88.0, 121.7, 126.1, 126.8,126.9, 127.0, 127.7, 127.9, 128.9, 131.26, 131.32, 131.8, 134.6, 137.0,140.1, 140.5, 150.9 ppm.

Example 43 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-butyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (254 mg, 0.85 mmol) and3-n-butylpyridine (0.5 mL) was heated at 60-70° C. for 12 hrs. Theresulted mixture was washed with diethyl ether and then dissolved inwater (20 mL). The aqueous solution was extracted with ethyl acetate (30mL×3). Water was removed by lyophilization to afford 263 mg of the titlecompound. Yield: 71%. ¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.2 Hz, 3H),1.36 (m, 2H), 1.63 (m, 2H), 2.44 (m, 2H), 2.67 (t, J=6.6 Hz, 2H), 2.84(t, J=7.8 Hz, 2H), 5.22 (t, J=6.9 Hz, 2H), 7.28-7.63 (m, 9H), 8.04 (dd,J=7.8, 6.0 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 9.39 (s, 1H), 9.49 (d, J=5.7Hz, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 16.7, 22.4, 30.5, 32.5,32.6, 60.9, 82.4, 88.0, 121.9, 126.9, 127.7, 128.0, 128.9, 132.0, 140.1,140.8, 142.9, 144.2, 144.3, 144.9 ppm.

Example 44 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-phenyl-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (207 mg, 0.69 mmol) and3-phenylpyridine (0.4 mL) was heated at 60-70° C. for 12 hrs. Theresulted mixture was washed with diethyl ether, and then dissolved inwater (30 mL). The aqueous solution was extracted with ethyl acetate (30mL×5). Water was removed by lyophilization to afford 206 mg of the titlecompound. Yield: 66%. ¹H NMR (300 MHz, CD3OD) δ 2.37 (m, 2H), 2.67 (t,J=6.3 Hz, 2H), 4.93 (t, J=6.9 Hz, 2H), 7.18-7.59 (m, 12H), 7.74 (m, 2H),8.09 (dd, J=8.1, 6.0 Hz, 1H), 8.65 (d, J=8.1 Hz, 1H), 9.05 (d, J=5.7 Hz,1H), 9.46 (s, 1H) ppm; ¹³C NMR (75 MHz, CD3OD) δ 17.5, 30.9, 62.6, 82.9,89.2, 123.2, 127.7, 128.5, 128.7, 129.4, 130.0, 130.6, 131.4, 133.1,134.2, 141.0, 141.6, 142.3, 144.0, 144.2 ppm.

Example 45 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-1-pyridinium bromide

A mixture of 4-(5-bromo-1-pentynl)-1,1′-biphenyl (162 mg, 0.54 mmol) andpyridine (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixturewas washed with diethyl ether and then dissolved in water (10 mL). Theaqueous solution was extracted with ethyl acetate (30 mL×3). Water wasremoved by lyophilization to afford 195 mg of the title compound. Yield:95%. ¹H NMR (300 MHz, CDCl₃) δ 2.42 (m, 2H), 2.67 (t, J=6.6 Hz, 2H),5.21 (t, J=6.9 Hz, 2H), 7.23-7.62 (m, 9H), 8.10 (t, J=6.9 Hz, 2H), 8.43(t, J=7.8 Hz, 2H), 9.64 (d, J=6.0 Hz, 2H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ16.7, 30.5, 60.9, 82.3, 87.8, 121.8, 126.8, 127.6, 128.4, 128.8, 132.0,139.9, 140.6, 145.27, 145.32 ppm.

Example 46 Synthesis of Compound [1,1′-biphenyl]-4-pentanol

5-(1,1′-biphenyl-4-yl)-4-pentyn-1-ol (3.89 g, 16.46 mmol) was dissolvedin methanol (30 mL), and 10% Pd/C (2.5% w/w) was added. The resultingmixture was hydrogenated on a Parr hydrogenation apparatus (45 psi) for4 hrs. The catalyst was removed by filtration through a Celite pad. Thefilter cake was rinsed with methanol, and the combined organic liquorswere concentrated under reduced pressure. The crude product was purifiedby column chromatography (hexanes:ethyl acetate 1:1) to afford 3.48 g ofthe title compound. Yield: 88%. ¹H NMR (300 MHz, CDCl₃) δ 1.35-1.48 (m,3H), 1.55-1.74 (m, 4H), 2.66 (t, J=7.5 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H),7.21-7.60 (m, 9H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 25.7, 31.5, 32.9, 35.8,63.1, 127.08, 127.13, 128.8, 128.9, 138.7, 141.2, 141.8 ppm.

Example 47 Synthesis of Compound 4-(5-bromopentyl)-1,1′-biphenyl

[1,1′-biphenyl]-4-pentanol (3.34 g, 13.90 mmol) and carbon tetrabromide(5.99 g, 18.07 mmol) were dissolved in dry methylene chloride (20 mL)and cooled to 0° C. Triphenyl phosphine (4.98 g, 18.07 mmol) inmethylene chloride (10 mL) was added dropwise, and the mixture wasstirred for 1 h at 0° C. The mixture was poured into hexanes (100 mL)and then filtered through a short silica gel column, washed withethylacetate/hexanes (1/4). The combined organic solvents wereevaporated to dryness under reduced pressure. The resulting residue waspurified by column chromatography (hexanes:ethylacetate 30:1) to afford4.18 g of the title compound. Yield: 99%. ¹H NMR (300 MHz, CDCl₃) δ 1.52(m, 2H), 1.67 (m, 2H), 1.91 (m, 2H), 2.67 (t, J=7.5 Hz, 2H), 3.41 (t,J=6.9 Hz, 2H), 7.21-7.60 (m, 9H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 28.2,30.9, 33.0, 34.1, 35.6, 127.1, 127.2, 128.8, 128.9, 138.8, 141.2, 141.5ppm.

Example 48 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-2-methyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (358 mg, 1.18 mmol) and2-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultingmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 393 mg of the titlecompound. Yield: 84%. ¹H NMR (300 MHz, CDCl₃) δ 1.53 (m, 2H), 1.71 (m,2H), 1.95 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 2.92 (s, 3H), 4.83 (t, J=8.1Hz, 2H), 7.20-7.60 (m, 9H), 7.89-8.02 (m, 2H), 8.38 (d, J=7.5 Hz, 1H),9.53 (d, J=6.0 Hz, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 20.9, 25.9, 30.6,30.8, 35.2, 58.3, 126.3, 126.8, 126.9, 127.0, 128.7, 128.8, 130.3,138.5, 140.7, 140.9, 145.2, 146.3, 154.1 ppm.

Example 49 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-methyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (358 mg, 1.18 mmol) and3-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 421 mg of the titlecompound. Yield: 90%. ¹H NMR (300 MHz, CDCl₃) δ 1.45 (m, 2H), 1.70 (m,2H), 2.08 (m, 2H), 2.59 (s, 3H), 2.63 (t, J=7.5 Hz, 2H), 4.92 (t, J=7.5Hz, 2H), 7.18-7.58 (m, 9H), 7.94 (t, J=7.2 Hz, 1H), 8.17 (d, J=8.1 Hz,1H), 9.26 (d, J=6.3 Hz, 1H), 9.46 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ18.8, 25.7, 30.7, 31.9, 35.2, 61.5, 126.8, 126.9, 127.0, 127.7, 128.3,128.7, 128.8, 138.5, 139.5, 140.7, 141.1, 142.1, 144.5, 145.5 ppm.

Example 50 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-4-methyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (348 mg, 1.15 mmol) and4-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 391 mg of the titlecompound. Yield: 86%. ¹H NMR (300 MHz, CDCl₃) δ 1.42 (m, 2H), 1.69 (m,2H), 2.04 (m, 2H), 2.57 (s, 3H), 2.62 (t, J=7.2 Hz, 2H), 4.85 (t, J=7.2Hz, 2H), 7.15-7.62 (m, 9H), 7.82 (d, J=6.0 Hz, 2H), 9.25 (d, J=6.0 Hz,2H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 22.3, 25.5, 30.7, 31.6, 35.2, 61.0,126.8, 126.9, 127.1, 128.7, 128.8, 128.9, 138.5, 140.7, 141.1, 144.0,158.7 ppm.

Example 51 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-2,4-dimethyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (331 mg, 1.09 mmol) and2,4-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 342 mg of the titlecompound. Yield: 77%. ¹H NMR (300 MHz, CDCl₃) δ 1.51 (m, 2H), 1.71 (m,2H), 1.92 (m, 2H), 2.55 (s, 3H), 2.65 (t, J=7.8 Hz, 2H), 2.84 (s, 3H),4.73 (t, J=7.8 Hz, 2H), 7.20-7.75 (m, 11H), 9.31 (d, J=6.3 Hz, 1H) ppm;¹³C NMR (75 MHz, CDCl₃) δ 20.1, 22.0, 25.8, 30.5, 30.8, 35.2, 57.4,126.7, 126.9, 127.0, 128.2, 128.6, 128.8, 130.4, 138.5, 140.7, 140.9,145.4, 152.8, 158.4 ppm.

Example 52 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3,4-dimethyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (322 mg, 1.06 mmol) and3,4-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 380 mg of the titlecompound. Yield: 87%. ¹H NMR (300 MHz, CDCl₃) δ 1.43 (m, 2H), 1.69 (m,2H), 2.05 (m, 2H), 2.46 (s, 3H), 2.48 (s, 3H), 2.62 (t, J=7.5 Hz, 2H),4.82 (t, J=7.2 Hz, 2H), 7.18-7.58 (m, 9H), 7.76 (d, J=6.3 Hz, 1H), 9.07(d, J=6.3 Hz, 1H), 9.29 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 17.1,20.4, 25.6, 30.7, 31.7, 35.2, 60.7, 126.8, 126.9, 127.0, 128.4, 128.7,128.8, 138.2, 138.5, 140.7, 141.1, 141.7, 143.3, 157.4 ppm.

Example 53 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3,5-dimethyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (352 mg, 1.16 mmol) and3,5-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resultingmixture was washed with diethyl ether and then dissolved in water (15mL). The aqueous solution was extracted with diethyl ether (30 mL×3).Water was removed by lyophilization to afford 406 mg of the titlecompound. Yield: 85%. ¹H NMR (300 MHz, CDCl₃) δ 1.45 (m, 2H), 1.70 (m,2H), 2.08 (m, 2H), 2.53 (s, 6H), 2.63 (t, J=7.8 Hz, 2H), 4.84 (t, J=7.5Hz, 2H), 7.18-7.58 (m, 9H), 7.93 (s, 1H), 9.21 (s, 1H) ppm; ¹³C NMR (75MHz, CDCl₃) δ 18.6, 25.8, 30.8, 31.9, 35.2, 61.3, 126.8, 126.9, 127.0,128.7, 128.8, 138.4, 138.7, 140.7, 141.1, 141.7, 146.0 ppm.

Example 54 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-quinolinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (328 mg, 1.08 mmol) andquinoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultingmixture was washed with diethyl ether and then dissolved in water (30mL). The aqueous solution was extracted with ethyl acetate (30 mL×5).Water was removed by lyophilization to afford 297 mg of the titlecompound. Yield: 64%. ¹H NMR (300 MHz, CDCl₃) δ 1.58 (m, 2H), 1.70 (m,2H), 2.13 (m, 2H), 2.62 (t, J=7.5 Hz, 2H), 5.37 (t, J=7.8 Hz, 2H),7.14-7.58 (m, 9H), 7.92 (d, J=7.5 Hz, 1H), 8.17 (m, 2H), 8.36 (m, 2H),9.13 (d, J=8.4 Hz, 1H), 10.33 (d, J=5.4 Hz, 1H) ppm; ¹³C NMR (75 MHz,CDCl₃) δ 26.1, 30.3, 30.9, 35.2, 58.1, 118.3, 122.5, 126.8, 126.9,127.1, 128.7, 128.8, 129.9, 130.1, 131.1, 136.0, 137.5, 138.5, 140.7,141.0, 147.3, 150.1 ppm.

Example 55 Synthesis of Compound2-[5-(1,1′-biphenyl-4-yl)-pentyl]-isoquinolinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (322 mg, 1.06 mmol) andisoquinoline (1 mL) was heated at 60-70° C. for 12 hrs. The resultedmixture was washed with diethyl ether and then dissolved in water (30mL). The aqueous solution was extracted with ethyl acetate (30 mL×5).Water was removed by lyophilization to afford 278 mg of the titlecompound. Yield: 61%. ¹H NMR (300 MHz, CDCl₃) δ 1.47 (m, 2H), 1.70 (m,2H), 2.17 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 5.07 (t, J=7.5 Hz, 2H),7.14-7.55 (m, 9H), 7.86 (m, 1H), 8.05 (m, 2H), 8.33 (d, J=6.9 Hz, 1H),8.70 (d, J=8.1 Hz, 1H), 8.79 (dd, J=6.9, 0.6 Hz, 1H), 10.93 (s, 1H) ppm;¹³C NMR (75 MHz, CDCl₃) δ 25.7, 30.7, 31.7, 35.2, 61.5, 126.3, 126.8,126.9, 127.0, 127.7, 128.7, 128.8, 131.15, 131.22, 134.4, 136.9, 137.2,138.5, 140.8, 141.0, 150.1 ppm.

Example 56 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-butyl-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (360 mg, 1.19 mmol) and4-n-butylpyridine (0.5 mL) was heated at 60-70° C. for 12 hrs. Theresulting mixture was washed with diethyl ether and then dissolved inwater (15 mL). The aqueous solution was extracted with ethyl acetate (30mL×3). Water was removed by lyophilization to afford 377 mg of the titlecompound. Yield: 72%. ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.2 Hz, 3H),1.29-1.53 (m, 4H), 1.60-1.80 (m, 4H), 2.08 (m, 2H), 2.63 (t, J=7.5 Hz,2H), 2.85 (t, J=7.8 Hz, 2H), 4.94 (t, J=7.5 Hz, 2H), 7.18-7.60 (m, 9H),8.00 (t, J=7.2 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 9.29 (d, J=6.0 Hz, 1H),9.30 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.9, 22.3, 25.7, 30.8,32.0, 32.5, 32.6, 35.2, 61.7, 126.8, 127.0, 127.1, 128.0, 128.8, 128.9,138.6, 140.8, 141.1, 142.5, 144.0, 144.1, 144.6 ppm.

Example 57 Synthesis of Compound1-[5-(1,1′-biphenyl-4-yl)-pentyl]-pyridinium bromide

A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (335 mg, 1.10 mmol) andpyridine (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixturewas washed with diethyl ether and then dissolved in water (15 mL). Theaqueous solution was extracted with diethyl ether (30 mL×3). Water wasremoved by lyophilization to afford 381 mg of the title compound. Yield:90%. ¹H NMR (300 MHz, CDCl₃) δ 1.44 (m, 2H), 1.69 (m, 2H), 2.07 (m, 2H),2.62 (t, J=7.5 Hz, 2H), 4.96 (t, J=7.5 Hz, 2H), 7.15-7.60 (m, 9H), 8.06(t, J=6.9 Hz, 2H), 8.42 (d, J=7.8 Hz, 1H), 9.48 (d, J=6.0 Hz, 2H) ppm;¹³C NMR (75 MHz, CDCl₃) δ 25.6, 30.7, 31.9, 35.2, 61.8, 126.8, 127.0,127.1, 128.4, 128.8, 128.9, 138.6, 140.8, 141.0, 145.0 ppm.

Example 58

Synthesis and structures of Mono-quaternary Ammonium CompoundsContaining Phenylene-acetylenic Moieties in the N-Alkyl Substituent

Example 59 Synthesis and Structures of Mono-Quaternary AmmoniumCompounds Containing Biphenylene-acetylenic or Biphenylene-AlkylenicMoieties in the N-Alkyl Substituent

Example 60 Synthesis and Structures of Mono-Quaternary AmmoniumCompounds Containing a Terminal 3-Pyridinyl Moiety

Example 61 Synthesis and Structures of Oxa Analogs of Mono-QuaternaryAmmonium Compounds

Example 62 Method for the In Vitro Inhibition of [³H]Nicotine Bindingand [³H]Methyllycaconitine (MLA) Binding

Test compounds of Formula (I), representing the mono quaternary nicotineanalogs of the present invention, were evaluated to determine the effectof a test compound on nicotine-binding and methyllycaconitine-bindingmediated by nicotine acetylcholine receptors. Table 1 of provides theresults of these binding assays.

Whole brain, excluding cortex and cerebellum, was homogenized in 20volumes of ice-cold buffer containing: 2 mM HEPES, 11.8 mM NaCl, 0.48 mMKCl, 0.25 mM CaCl₂, and 0.12 mM MgSO₄, pH 7.5. Homogenate wascentrifuged (25,000 g, 15 min, 4° C.). Pellets were resuspended in 20volumes of buffer and incubated at 37° C., for 10 min, cooled to 4° C.and centrifuged (25,000 g, 15 min, 4° C.). Pellets were resuspended andcentrifuged using the same conditions. Final pellets were stored inassay buffer, containing: 20 mM HEPES, 118 mM NaCl, 4.8 mM KCl, 2.5 mMCaCl₂, and 1.2 mM MgSO₄, pH 7.5 at −70° C. Upon use, final pellets wereresuspended in ˜20 volumes of assay buffer. Samples (250 μl) contained100-140 μg of membrane protein, 3 nM [³H]nicotine or 3 nM[³H]methyllycaconitine (MLA), and test compounds of Formula (I) (100 nM)in assay buffer containing 50 mM Tris. A control sample absent testcompounds of Formula (I) was also prepared. In the [³H]nicotine-bindingassay and [³H]MLA-binding assay, nonspecific-binding was determined inthe presence of 10 μM nicotine and 10 μM MLA, respectively. Incubationsproceeded for 60 min at a room temperature using 96-well plates, andwere terminated by harvesting on Unifilter-96 GF/B filter platespresoaked in 0.5% polyethylenimine, using a Packard FilterMateharvester. After washing 5 times with 350 μl ice-cold assay buffer, thefilter plates were dried (60 min, 4° C.), bottom-sealed, and filled withPackard's MicroScint 20 cocktail (40 μl/well). After 60 min, filterplates were top-sealed, and levels of radioactivity were determinedusing a Packard TopCount. Protein concentrations were determined usingthe Bradford dye-binding procedure using bovine serum albumin as astandard protein.

Example 63 Method for the Analysis of Rat Striatal Slices for Inhibitionof Nicotine-Evoked [³H]Neurotransmitter Release

Rat striatal slices (500 μm thickness, 6-8 mg wet weight) were incubatedfor 30 minutes in Krebs buffer (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl₂,1.0 mM NaH₂PO₄, 1.3 mM CaCl₂, 11.1 mM glucose, 25 mM NaHCO₃, 0.11 mML-ascorbic acid, and 0.004 mM disodium EDTA at pH 7.4, and saturatedwith 95% O₂/5% CO₂) in a metabolic shaker at 34° C. Slices were rinsedwith 15 mL of fresh buffer, and were incubated for an additional 30minutes in fresh buffer containing 0.1 μM [³H]dopamine (DA; 6 slices/3mL). Subsequently, slices were rinsed with 15 mL of fresh buffer andtransferred to a glass superfusion chamber. Slices were superfused (1.0mL/min) for 60 minutes with Krebs buffer containing nomifensine (10 μM)and pargyline (10 μM), and maintained at 34° C., pH 7.4, with continualaeration (95% O₂/5% CO₂). Two five minute samples (5 mL each) werecollected to determine basal outflow of [³H]DA. The test compounds ofFormula (I) were added to the superfusion buffer after the collection ofthe second sample, and were maintained in the buffer until 12consecutive five minute samples were collected. Subsequently,S-(−)-nicotine (10 μM) was added to the buffer, and an additional 12consecutive five minute samples were collected. At the end of theexperiment, each slice was solubilized, and the [³H]content of thetissue determined.

Radioactivity in the superfusate and tissue samples was determined byliquid scintillation spectroscopy. Fractional release of tritiumcollected in each sample was divided by the total tritium present in thetissue at the time of sample collection, and the fractional release oftritium collected was expressed as a percentage of total tritium. Basal[³H]outflow was calculated from the average of the tritium collected inthe two five minute samples just before addition of a test compound ofFormula (I). The sum of the increase in collected tritium resulting fromeither exposure to a test compound of Formula (I), or exposure to S(−)nicotine in the absence and presence of a test compound of Formula (I)equaled total [³H]overflow. [³H]Overflow was calculated by subtractingthe [³H]outflow during an equivalent period of pre-stimulation from thevalues in samples collected during and after drug exposure. Inasmuch asthe radio-labeled compounds were not separated and identified, thetritium collected in superfusate is referred to as either [³H]outflow or[³H]overflow, rather than as [³H]DA. [³H]Overflow primarily represents[³H]DA in the presence of nomifensine and pargyline in the superfusionbuffer.

The mono quaternary analogs of Formula (I) were evaluated for theirability to evoke [³H]DA release from rat striatal slices. In addition,the classical competitive nicotinic antagonist DHβE was also examined inthis assay for comparison. None of the compounds examined had anysignificant [³H]DA releasing properties in this assay in theconcentration range tested.

The quaternary analogs of Formula (I) were also evaluated for theirability to inhibit NIC-evoked [³H]DA release. In these experiments, thestriatal slices were superfused for 60 minutes with 100 nM concentrationof the quaternary analogs prior to NIC (10 μM) exposure. Antagonistactivity was evaluated by comparing the NIC-evoked [³H]overflow in theabsence and presence of the analogs. The relative order of potency ofthe quaternary analogs of Formula (I) for inhibition of NIC-evoked[³H]DA release from rat striatal slices is illustrated in Table 1.

TABLE 1 Inhibition of [³H]NIC and [³H]MLA Binding to Rat StriatalNicotinic Receptors and Inhibition of Nicotine-evoked [³H]DopamineRelease from Superfused Rat Striatal Slices by Mono Quaternary AmmoniumSalts of Formula (I). Inhibition of Inhibition of Inhibition ofNicotine- [³H]Nicotine [³H]MLA evoked [³H]DA TEST COMPOUND OF FORMULA(I) binding binding release

  0%^(a)   0%^(a)   62%^(a)

0% 0% ND

0% 0% 11%

4% 2% 33%

0% 2% 31%

K_(i) > 100 Ki > 100  0%

Ki > 100 Ki; 27 ± 11 12%

6% 3% 11%

5% 0% 58%

0% 0% ND

Ki > 100 Ki; 3.7 ± 0.3 70   

Ki > 100 Ki; 14 ± 3.7 ND

Ki > 100 Ki; 7.2 ± 1.0  0%

0% 0% ND

0% 0% 64   

6% 0% 19%

0% 9% 14%

0% 10%  ND

3% 0% 20%

0% 0% ND

0% 0% ND

0% 0% ND

0% 0% 35%

2% 7% 45%

ND ND 45%

0    2% 41%

4% 7% 55%

ND ND 18%

0% 3% 40%

8% 3% 51%

ND ND 51%

0% 8% 20%

ND ND 38%

2% 6%  5%

ND ND 39%

1% 7% 23%

ND ND 61%

0% 6% ND

0% 6% ND

20%  6% 47%

ND ND 51%

0% 9% 50%

ND ND 43%

8% 6% ND

2% 6% 34%

ND ND 30%

^(a)Data are % inhibition at 100 nM concentration of the mono quaternaryanalogs for at least 1-3 independent experiments; with the exception ofwhen a Ki value in μM is provided, in which case a full concentrationeffect was evaluated. Specific binding in the [³H]NIC binding assay iscalculated as the difference between the total binding of 3 nM [³H]NICand nonspecific binding in the presence of 10 μM cold nicotine. Specificbinding for the [³H]MLA binding assay is calculated as the differencebetween the total binding of 2.5 nM [³H]MLA to the receptors alone andits nonspecific binding in the presence of 1 μM cold MLA. Analog-inducedinhibition of nicotine-evoked [³H]DA release is calculated as a percentof that in the absence of the mono quaternary ammonium analog. NDindicates not determined.

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andthe scope of the invention. All such modifications and variations oreintended to be included herein within the scope of this disclosure andthe present invention and protected by the following claims.

We claim:
 1. A mono quaternary ammonium compound of formula:

wherein A¹, A², A³, A⁴, and A⁵ are each carbon; wherein R¹, R², R³, R⁴,and R⁵ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, halo, cyano, and nitro; wherein Z¹ is selected from the groupconsisting of alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,phenylene, substituted phenylene, alkoxy, and substituted alkoxy;wherein Z² is selected from the group consisting of substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, arylene, substituted arylene, heterocycle,substituted heterocycle, alkoxy and substituted alkoxy; wherein Z³ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, andsubstituted heterocycle; and wherein X⁻ is an inorganic or organicanion.
 2. The compound of claim 1, wherein A¹, A², A³, A⁴, and A⁵ arecarbon; wherein R¹ is hydrogen or methyl; wherein R² is hydrogen,methyl, ethyl, butyl, phenyl, or bromo; wherein R³ is hydrogen ormethyl; wherein R⁴ is hydrogen or methyl; wherein R⁵ is hydrogen;wherein Z¹, butyl, but-3-ynyl, pentyl, pent-4-ynyl or 2-ethoxy; whereinZ² is para-phenylene or 2-ethoxy; wherein Z³ is propyl, butyl,but-1-ynyl, hex-1-ynyl, phenyl, or 3-pyridinyl; and wherein X ischloride, bromide or iodide.
 3. The compound of claim 1, wherein A¹, A²,A³, A⁴, and A⁵ are carbon; wherein R¹ is hydrogen or methyl; wherein R²is hydrogen, methyl, ethyl, or bromo; wherein R³ is hydrogen or methyl;wherein R⁴ is hydrogen or methyl; wherein R⁵ is hydrogen; wherein Z¹ is,butyl, but-3-ynyl, pent-4-ynyl or 2-ethoxy; wherein Z² is para-phenyleneor 2-ethoxy; wherein Z³ is propyl, butyl, but-1-ynyl, hex-1-ynyl,phenyl, or 3-pyridinyl; and wherein X is chloride, bromide or iodide. 4.The compound of claim 1, wherein A¹, A², A³, A⁴, and A⁵ are carbon;wherein R¹ is hydrogen or methyl; wherein R² is hydrogen, methyl, butyl,or phenyl; wherein R³ is hydrogen or methyl; wherein R⁴ is hydrogen ormethyl; wherein R⁵ is hydrogen; wherein Z¹ is pentyl or pent-4-ynyl;wherein Z² is para-phenylene; wherein Z³ is phenyl; and wherein X isbromide.
 5. The compound of claim 1 selected from the group consistingof: 1-[4-(4-butyl-phenyl)-butyl]-2-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-4-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-2,4-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3,4-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-butyl]-3,5-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-4-methyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-ethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3,4-dimethyl-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3,5-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-2-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-4-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-2,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3,5-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-butyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-3-phenyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pent-4-ynyl]-1-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-2-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-4-methyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-2,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3,4-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3,5-dimethyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-3-butyl-pyridinium bromide;1-[5-(1,1′-biphenyl-4-yl)-pentyl]-pyridinium bromide;3-methyl-1-[5-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;2-methyl-1-[5-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;4-methyl-1-[5-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;3,4-dimethyl-1-[5-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide;3,5-dimethyl-1-[5-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide; and2,4-dimethyl-1-[5-(4-propyl-phenyl)-pent-4-ynyl]-pyridinium bromide. 6.A composition comprising a pharmaceutically acceptable carrier and acompound of claim
 1. 7. A composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 2. 8. A compositioncomprising a pharmaceutically acceptable carrier and a compound of claim3.
 9. A composition comprising a pharmaceutically acceptable carrier anda compound of claim
 4. 10. A composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 5. 11. The compound of claim1 selected from the group consisting of:1-[2-(2-hexoxy-ethoxy)-ethyl]-3-methyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-4-methyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-3,4-dimethyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-3,5-dimethyl-pyridinium chloride;1-[2-(2-hexoxy-ethoxy)-ethyl]-2-methyl-pyridinium chloride; and1-[2-(2-hexoxy-ethoxy)-ethyl]-2,4-dimethyl-pyridinium chloride.
 12. Acompound selected from the group consisting of:1-[4-(4-butyl-phenyl)-butyl]-3-(3-hydroxy-propyl)-pyridinium bromide;1-[4-(4-butyl-phenyl)-but-3-ynyl]-3-(3-hydroxy-propyl)-pyridiniumbromide; 1-dodec-7-ynyl-2-methyl-pyridinium iodide;1-dodec-7-ynyl-3-methyl-pyridinium iodide;1-dodec-7-ynyl-4-methyl-pyridinium iodide;1-dodec-7-ynyl-2,4-dimethyl-pyridinium iodide;1-dodec-7-ynyl-3,5-dimethyl-pyridinium iodide;1-dodec-7-ynyl-3,4-dimethyl-pyridinium iodide;1-dodec-9-ynyl-2-methyl-pyridinium bromide;1-dodec-9-ynyl-3-methyl-pyridinium bromide; and1-dodec-9-ynyl-4-methyl-pyridinium bromide;2-methyl-1-(8-phenyl-octyl)-pyridinium bromide;3-methyl-1-(8-phenyl-octyl)-pyridinium bromide;2,4-dimethyl-1-(8-phenyl-octyl)-pyridinium bromide;4-methyl-1-(8-phenyl-octyl)-pyridinium bromide;3-methyl-1-[13-(3-pyridinyl)-tridecyl]-pyridinium bromide;3,4-dimethyl-1-[13-(3-pyridinyl)-tridecyl]-pyridinium bromide;3,5-dimethyl-1-[13-(3-pyridinyl)-tridecyl]-pyridinium bromide;3-methyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;4-methyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;3-bromo-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide;3,4-dimethyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide; and3,5-dimethyl-1-[12-(3-pyridinyl)-dodecyl]-pyridinium bromide.